6-(1-carbamoyl-1-hydroxymethyl)penicillanic acid derivatives

ABSTRACT

6-(1-Carbamoyl-1-hydroxymethyl)penicillanic acid derivatives are useful as antibacterials and/or beta-lactamase inhibitors.

BACKGROUND OF THE INVENTION

6-(1-Carbamoyl-1-hydroxymethyl)penicillanic acid derivatives, having thepartial structure ##STR1## wherein n is 0, 1 or 2, are generally usefulas antibacterials and/or beta-lactamase inhibitors. Some of thesecompounds possess excellent antibacterial activity per se, and so arevaluable as industrial or medicinal antibacterial agents in their ownright. Additionally, and more generally, they have particular value asbeta-lactamase inhibitors; as such, they are useful in combination withconventional beta-lactam antibiotics (penicillins and cephalosporins)against microorganisms resistant or partially resistant to beta-lactamantibiotics through production of beta-lactamase enzymes.

beta-Lactamase inhibiting 6-(1-hydroxyalkyl)penicillanic acid1,1-dioxides (sulfones) and 3-carboxylate esters thereof have beenreported by Kellogg (U.S. Pat. Nos. 4,287,181; 4,342,768; European Pat.Publication No. 83977), while 6-(aminoacyloxymethyl)penicillanic acid1,1-doxides have been reported by Barth (U.S. Pat. No. 4,503,040).Various antibacterial 6-(1-hydroxyalkyl)penicillanic acids and their1-oxides (sulfoxides) have been disclosed by Beattie et al., (U.S. Pat.No. 4,207,323), but that disclosure encompasses no compounds containingthe key 6-(1-carbamoyl-1-hydroxyalkyl)substituent of the presentinvention.

U.K. Patent Application No. 2,053,220 broadly discloses beta-lactamaseinhibiting compounds of the formula ##STR2## The definitions of R_(a),R_(b) and R_(c) define literally an infinite number of compounds. Saidinfinity of compounds proposed might be construed to encompass some ofthe 1,1-dioxide compounds of the present invention. However, there is nospecific mention of or preparative method provided for any compounds ofthe type of the present invention, let alone any hint or suggestion thatthe present compounds represent preferred compounds, having potentantibacterial and/or beta-lactamase inhibitory activity.

Sheehan et al. [J. Antibiotics Japan, vol. 37, pp. 1441-1448 (1984)]have reported that 6-[1-(N-phenylcarbamoyl)methyl]penicillanic, acompound lacking the present 1-hydroxy group, possesses only limitedGram-positive activity and no Gram-negative activity. Sheehan et al. donot list the latter compound among those having a modicum ofbeta-lactamase inhibitory activity.

SUMMARY OF THE INVENTION

The present invention is concerned with antibacterials, beta-lactamaseinhibitors and/or intermediates containing the following partialstructure: ##STR3## wherien n is 0, 1 or 2. Because of their excellentactivity, the present invention is particularly concerned withantibacterial and/or beta-lactamase inhibitory compounds having theformula ##STR4## wherein

n is 0, 1 or 2;

R is hydrogen, a radical group forming an ester hydrolyzable underphysiological conditions, or an acyloxymethyl or 1-(acyloxy)ethylradical derived from a conventional beta-lactam antibiotic; and

R¹ and R² are taken separately and are each independently hydrogen, (C₁-C₇)alkyl, phenyl, (C₇ -C₁₂)phenylalkyl, (C₃ -C₇)cycloalkyl, naphthyl,or ##STR5## where m is 1 or 2 and p is 2 or 3; or one of said groupssubstituted on aliphatic, aromatic or heterocyclic carbon with (C₁-C₄)alkyl, phenyl, hydroxy, hydroxymethyl, 2-hydroxyethyl, (C₁-C₄)alkoxy, (C₂ -C₅)alkanoyloxy, carbamoyloxy, formamido, (C₂ -C₅)alkanecarboxamido, (C₁ -C₄)alkanesulfonamido, ##STR6## on heterocyclicnitrogen with (C₁ -C₄)alkyl,phenyl, (C₇ -C₉)phenylalkyl, pyridyl,2-hyroxyethyl, formyl, (C₂ -C₅)alkanoyl or ##STR7## R¹ and R² are takentogether with the nitrogen to which they are attached to form apyrrolidine, piperidine, perhydroazepine, morpholine, piperazine,homopiperazine, indoline, isoindoline, 1,2,3,4-tetrahydroquinoline,1,2,3,4-tetrahydroisoquinoline or ##STR8##(1,4-diazabicyclo[3.2.2]non-4-yl) ring system; or one of said ringsystems substituted on aliphatic, aromatic or heterocyclic carbon with(C₁ -C₄)alkenyl, phenyl, hydroxy, hydroxymethyl, 2-hydroxyethyl, (C₁-C₄)alkoxy, (C₂ -C₅)alkanoyloxy, carbamoyloxy, formamido, (C₂-C₅)alkanecarboxamido, (C₁ -C₄)alkanesulfonamido, ##STR9## onheterocyclic nitrogen with (C₁ -C₄)alkenyl, phenyl, (C₇ -C₉)phenylalkyl,pyridyl, 2-hydroxyethyl, formyl, (C₂ -C₅)alkanoyl or ##STR10## R³ and R⁴are taken separately and are each hydrogen, (C₁ -C₄)alkyl or phenyl; orR³ and R⁴ are taken together with the nitrogen to which they areattached to form a pyrrolidine, piperidine, morpholine, or 4-[(C₁-C₃)alkyl or phenyl]piperazine ring; with the provisos that in saidgroup --NR¹ R² (a) there is no tetrahedral carbon atom which issimultaneously bonded to two of the same or different atoms selectedfrom the group consisting of nitrogen, oxygen and sulfur and (b) whenboth of R¹ and R² are other than hydrogen, then the carbons of R¹ and R²which are adjacent to the nitrogen branch point are substituted with atotal of at least two hydrogens;

a pharmaceutically acceptable cationic salt when the compound contains acarboxylic acid group; or

a pharmaceutically acceptable acid addition salt when the compoundcontains a basic nitrogen atom.

Preferred compounds are those which are readily prepared and show a highlevel of the desired activity.

When R¹ and R² are taken separately, the preferred values are eachindependently hydrogen, (C₁ -C₄)alkyl, (C₅ -C₆)cycloalkyl, phenyl,benzyl or one of said groups substituted by methyl, hydroxy, (C₁-C₂)alkoxy, --COOR³, or --CONR³ R⁴. When n is 0, most preferred are R¹as methyl or ethyl with R² as methyl, ethyl, phenyl or benzyl; R¹ asbenzyl and R² as --CH₂ CONHCH₃ ; and R¹ as ethyl and R² as3-hydroxyphenyl. When n is 1, R¹ and R² as each methyl with the 1-oxidein the beta-configuration is most preferred. When n is 2, most preferredare R¹ as methyl with R² as methyl, phenyl or cyclohexyl.

When R¹ and R² are taken together with the nitrogen to which they areattached, the preferred ring systems are pyrrolidine, piperidine,perhydroazepine, morpholine, 4-[(C₁ -C₄)alkyl, phenyl, benzyl, pyridylor 2-hydroxyethyl]piperazine, indoline, isoindoline,1,2,3,4-tetrahydroquinoline or 1,2,3,4-tetrahydroisoquinoline ringsystem, or one of said ring systems substituted by methyl, hydroxy,hydroxymethyl, carboxy, carbamoyl, --COOR³ or --CONR³ R⁴. When n is 0,most preferred are R¹ R² N-- as piperidino, perhydroazepin,1,2,3,4-tetrahydroisoquinolino, isoindolino and indolino. When n is 1 R¹R² N-- as pyrrolidino with the 1-oxide in the alpha configuration ismost preferred. When n is 2, most preferred is R¹ R² N-- as piperidino,4-hydroxypiperidino or 4-phenylpiperidino.

In all cases, the most preferred compounds further have the 1-hydroxysubstituted carbon of the side chain in the S-configuration: ##STR11##

Pharmaceutically-acceptable acid addition salts include, but are notlimited to, those with hydrochloric acid, sulfuric acid, nitric acid,phosphoric acid, citric acid, maleic acid, succinic acid,benzenesulfonic acid, p-toluenesulfonic acid, 2-naphthalenesulfonic acidand methanesulfonic acid. Pharmaceutically-acceptable cationic saltsinclude, but are not limited to, those of sodium, potassium, calcium,N,N'-dibenzylethylenediamine, N-methylglucamine (meglumine) anddiethanolamine. The preferred cationic salts are those of potassium andsodium.

The reference to esters which are hydrolyzable under physiologicalconditions refers to those esters frequently referred to as "pro-drugs".Such esters are now as well-known and common in the penicillin art aspharmaceutically-acceptable salts. Such esters are generally used toenhance oral absorption, but in any event are readily hydrolyzed in vivoto the parent acid. The more preferred ester forming radicals are thosewherein R is:

(5-methyl-1,3-dioxol-2-on-4-yl)methyl;

1H-isobenzofuran-3-on-1-yl;

gamma-butyrolacton-4-yl;

--CHR⁵ OCOR⁶ ; or

--CHR⁵ OCOOR⁷ ;

wherein R⁵ is hydrogen or methyl; R⁶ is (C₁ -C₆)alkyl, (C₁-C₆)carboxalkyl, carboxycyclohexyl or carboxyphenyl; and R⁷ is (C₁-C₆)alkyl. The most preferred radicals are pivaloyloxymethyl and1-(ethoxycarbonyloxy)ethyl.

The reference to an acyloxymethyl or 1-(acyloxy)ethyl ester derived froma conventional beta-lactam antibiotic refers to a mixed methanediol or1,1-ethanediol ester of the formula (I) wherein R is derived from one ofthe standard, well known beta-lactam antibiotics containing a carboxylicacid group on the carbon alpha to the beta-lactam ring nitrogen, i.e., Ris a group ##STR12## Preferred esters of this class are those wherein Ris: ##STR13## wherein Y is hydrogen or hydroxy.

The present invention also encompasses a pharmaceutical composition fortreating bacterial infections which comprises in a weight ratio of 10:1to 1:3 a conventional beta-lactam antibiotic and a compound of theformula (I) wherein R¹ is hydrogen or a radical group forming an esterwhich is hydrolyzable under physiological conditions. For thiscomposition, preferred compounds of the formula (I) are defined above.Preferred beta-lactam antibiotics are penicillins or cephalosporins ofestablished clinical utility, viz., amoxicillin, ampicillin, apalcillin,azlocillin, bacampicillin, carbenicillin, carbenicillin indanyl,carbenicillin phenyl, cefaclor, cefadroxil, cefaloram, cefamandole,cefamandole nafate, cefaparole, cefatrizine, cefazolin, cefbuperazone,cefmenoxime, cefonicid, cefodizime, cefoperazone, ceforanide,cefotaxime, cefotiam, cefoxitin, cefpimazole, cefpiramide, cefpirome,cefsulodin, ceftazidime, ceftizoxime, ceftriaxone, cefuroxime,cephacetrile, cephalexin, cephaloglycin, cephaloridine, cephalothin,cephapirin, cepharidine, cyclacillin, epicillin, furazlocillin,hetacillin, lenampicillin, levopropylcillin, mecillinam, mezlocillin,penicillin G, penicillin V, phenethicillin, piperacillin, pivampicillin,sarmoxicillin, sarpicillin, suncillin, talapicillin and ticarcillin,including the pharmaceutically acceptable salts thereof. The namesemployed for these beta-lactams are generally USAN, i.e., U.S. AdoptedNames.

Also preferred are combinations of the beta-lactamase inhibitors of theinvention with7-[D-(2-[4-carboxy-5-imidazolecarboxamido])-2-phenylacetamido]-3-[4-(2-sulfonatoethyl)pyridinium]-3-cephem-4-carboxylicacid or azetreonam.

The present invention further encompasses a method of treating abacterial infection in a mammal by topical, oral or parenteraladministration of an antibacterially effective amount of apharmaceutical composition of the preceding paragraphs; a pharmaceuticalcomposition comprising an antibacterially effective amount of a compoundof the formula (I) per se, and a method of treating bacterial infectionswith an antibacterially effective amount of a compound of the formula(I) per se.

The present invention also encompasses intermediate compounds asfollows: ##STR14## wherein q is 0 or 2 and n, R¹ and R² are generally asdefined above, but with the further proviso that when said group --NR¹R² contains a substituent --NH or --NH₂ group which is more reactivetoward cyclic anhydride than the R¹ R² NH nitrogen, said substituent--NH or --NH₂ group is protected by a benzyloxycarbonyl group.

Particularly when compounds of the formula (II) are prepared by aGrignard reaction employing a compound of the formula ##STR15## saidcompound and derived compounds of the formula (II) and (III) willgenerally have phenolic hydroxy and carboxy groups protected by a benzylgroup, i.e., as the corresponding benzyl ether or benzyl ester,respectively.

Finally, the present invention encompasses compounds of the formula##STR16## wherein

q is 0 or 2;

R⁸ and R⁹ are taken separately and R⁸ is hydrogen and R⁹ is allyl, or R⁸and R⁹ are taken together and are ##STR17## and

X is hydrogen or bromo;

with the proviso that when X is hydrogen, it is of 6-alphaconfiguration.

The preferred intermediates of this class are: ##STR18## Most preferredof these of the formulas (IV), (V), (VI) and (VII) are those wherein qis 0. The preferred configuration for the side chain in these compoundsis ##STR19## which is the S-configuration in the case of compounds (V),(VI) and (VII) and the R-configuration in the case of compound (IV).

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the formula (I) are preferably prepared by thefollowing synthetic routes: ##STR20## Variations in this sequence, e.g.,cyclic anhydride formation and amide formation prior to debromination,will be readily evident to those skilled in the art. To make compoundswherein the group R¹ R² N-- contains a basic --NH₂ of >NH function, itis preferred to use the cyclic anhydride (VII). It is similarlypreferred to make compounds wherein the group R¹ R² N-- contains acidicOH groups (particularly phenolic or carboxylic acid groups) via thecyclic anhydride (VII). Alternatively, the latter groups are protectedas benzyl ethers or esters, respectively, in the reaction of theGrignard reagent with the glyoxamide.

In the first stage of the above synthetic route, the known dibromocompound (VIII) is dissolved in a dry, reaction-inert solvent such astetrahydrofuran or toluene, which will remain liquid at the reactiontemperature, cooled to -50° to -100° C., and reacted with substantiallyone molar equivalent of a Grignard reagent such as methylmagnesiumbromide in an ethereal solvent such as diethyl ether (said reagentformed by standard methods in the laboratory, or purchasedcommercially), generally added portionwise over a 5-15 minutes whilemaintaining the same low reaction temperature. After stirring for 10-30minutes to allow complete reaction and equilibration, the glyoxylateamide or ester, ##STR21## is added, optionally dissolved in the same oranother reaction inert solvent, in like manner. After stirring 10minutes-1 hour at the same low temperature, the reaction mixture isquenched with a weak acid such as acetic acid or an acidic salt such asammonium chloride, and product isolated by standard methods such asevaporation, extraction and chromatography, including opticalchromatographic separation of epimers corresonding to R- and S- sidechain configurations: ##STR22## where stability and differences inpolarity permit.

As used here and hereinafter, the expression "reaction-inert solvent"refers to any solvent which does not interact with starting materials,reagents, intermediates or products in a manner which significantlyreduces the yield of the desired product.

When the allyl esters of the formula (IV) are prepared, the requiredallyl glyoxylate is preferably prepared according to specific methodsdetailed below. When the amides of the formula (II) are prepared, therequired glyoxylate amides are generally prepared by lead tetraacetateoxidation of the corresponding bis-amide of tartaric acid, asspecifically exemplified below. The tartrate bis-amides are in turnavailable from tartaric acid and its reactive diesters (e.g. dimethyltartrate) and amines by standard methods.

The C.6 stereochemistry of the intermediates of the formulas (II) and(IV) has not been determined and is therefore not specified. However,C.6 stereochemistry becomes fixed as 6-beta in (III) and (V) during thetributyltin hydride debromination step, regardless of stereochemistry atthe 6-position in the precursor. The debrominaton step is optionallycarried out in the presence of small amounts of free radical initiatorsuch as 2,2'-azobisisobutyronitrile (AIBN), in a reaction inert solventsuch as benzene or toluene. The temperature is usually elevated (e.g.,60°-100° C.), such that reaction occurs in a reasonable period of time,but not so high as to cause undue thermal degradation. Products are onceagain recovered and purified by standard methods, as noted above, withchromatographic separation of R- and S-sidechain epimers alternativelycarried out at this stage.

When the allyl ester (V) is employed as intermediate, it is converted tothe acid (VI), conveniently by reaction with substantially one molarequivalent of sodium or potassium ethylhexanoate (or other lipophiliccarboxylate salt) in the presence of catalytic amount oftetrakis(triphenylphosphine)palladium (typically 5 mole %) andtriphenylphosphine (typically 20-25 mole %) in a reaction inert solvent,preferably one in which the reactants are soluble and the alkali metalsalt of the desired product is relatively insoluble. Particularly wellsuited in the present instance is the sodium salt of 2-ethylhexanoate inethyl acetate as solvent. In this case the salt is fully precipitated byaddition of a lipophilic solvent such as ether.

Temperature is not critical in this deprotection step, e.g., 0°-50° C.is usually satisfactory. Most conveniently, ambient temperature isemployed. If desired, the salt is converted to the free acid form,during or after isolation, by standard methods, e.g., acidification ofan aqueous solution of the salt, with extraction of the free acid into awater immiscible organic solvent.

The acid compound (VI), conveniently in the form of its sodium salt, isreadily converted to the cyclic anhydride (VII) by the action ofsubstantially one molar equivalent of phosgene, in a reaction inertsolvent such as tetrahydrofuran or carbon tetrachloride. If desired, theanhydride is isolated, e.g., by simple stripping of solvent from thereaction. Alternatively, and preferably, the solution of anhydride, withat least 1 (usually 2) molar equivalents of a tertiary amine such asdiisopropylethylamine added to neutralize by-product HCl, is useddirectly in the next step.

In the next stage, the anhydride with or without isolation, is reactedwith an amine, R¹ R² NH, to form the intermediate6-(1-carbamoyl-1-hydroxymethyl)penicillanate of the formula (III), inthe same, or another reaction inert solvent such as tetrahydrofuran,methylene dichloride or, when the amine is highly reactive, even H₂ O.Temperature is not critical, but will generally be in the range -25° to50° C. With highly reactive amines such as NH₃, temperatures lower inthis range are preferred, while with less reactive amines, such asN-benzylaniline, temperatures higher in the range can be beneficial. Ingeneral, ambient temperatures are perfectly satisfactory. At least 1molar equivalent of the amine is employed, although an excess, up to 3or 4 molar equivalents, is beneficially used when the amine isrelatively unreactive, particularly when the amine is readily available.According to the present invention, the present products of the formula(I) can contain a substituent primary or secondary amine function in thegroup R¹ R² N--. When that amine substituent is more reactive towardsthe cyclic anhydride than amino group R¹ R² NH, it is strongly preferredto protect that more reactive amine as its benzyloxycarbonyl derivative(readily prepared by reaction with one equivalent of benzyloxycarbonylchloride). For example, when R¹ is ethyl and ##STR23## is employed asthe reactant. Just to the contrary, when the amine substituent isunreactive or less reactive than the group R¹ R² NH, it is preferred tosimply react the unprotected diamine with the cyclic anhydride. Forexample, when R¹ R² N-- is (CH₃)₃ CnHCH₂ CH₂ N(CH₃)--, (CH₃)₂ CHNHCH₂CH₂ NH--, (CH₃)₂ CHNHCH(CH₃)CH₂ NH--, (C₆ H₅)NHCH₂ CH₂ NH-- or ##STR24##it is preferred to react the unprotected amine directly with theanhydride, thereby avoiding the unnecessary and generally difficultsteps of protecting the less reactive amine function of a diamine.

The amines required for the present syntheses are readily available.They are known from the prior art, frequently available from commercialsources, or are prepared by methods analogous to those found in theprior art.

If 1-oxide or 1,1-dioxide is desired, and sulfur is not already in thedesired oxidation state, the sulfur is oxidized at this stage in thesynthetic sequence. In order to avoid unduly complex mixtures when the1-oxides (sulfoxides) are desired, said oxidation is preferably carriedout on separated R- or S-sidechain epimers. To form a mixture of the1-alpha-oxide (S O) and 1-beta-oxide (S O) of the formula (III) whereinn is 1, the corresponding sulfides (III, n=0) are oxidized withsubstantially 1 molar equivalent of a peracid, convenientlym-chloroperbenzoic acid, in a reaction-inert solvent such as methylenechloride or ethyl acetate, at 0°-50° C., conveniently at ambienttemperatures. The resulting mixture is isolated by standard methods suchas extraction, evaporation, crystallization and chromatography,including chromatographic separation of the 1-alpha and 1-beta-oxides atthis or a later stage of the synthetic sequence, as desired. To form the1,1-dioxide (sulfone) of the formula (II) wherein n=2, the sulfide isoxidized with at least two molar equivalents of the peracid, otherwiseunder conditions and with isolation as described above for sulfoxides.

In the final stage of the synthesis of the compounds (I) wherein R ishydrogen, the C.2 benzyl ester group, together with any other benzylester, benzyl ether or N-benzyloxycarbonyl group, is removed byhydrogenolysis using methods generally known in the penicillin art. Thesubstrate, in a reaction-inert solvent, is contacted with hydrogen inthe presence of a noble metal catalyst, such as palladium, platinum orrhodium, optionally in the form of its oxide or a salt, or on a carriersuch as carbon, an alkaline earth carbonate or alumina. Temperature isnot critical (e.g. 0°-50° C.), but is preferably 25° C. or lower inorder to minimize thermal degradation. Pressure can be varied over awide range (subatmospheric to 100 atmospheres), but as a matter ofconvenience will generally be in the range of 1 to 7 atmospheres. Thereaction inert solvent is preferably relatively low boiling so as to bereadily removed by concentration in vacuo. Aqueous tetrahydrofuran is asolvent particularly well-suited for the present purpose. The preferredcatalyst is palladium, supported on carbon. It is further preferred tocarry out the hydrogenation in the presence of substantially oneequivalent of sodium bicarbonate. Following recovery of the catalyst,tetrahydrofuran is stripped away and the aqueous residue freeze dried todirectly yield the sodium salt of the product. If the free acid then isdesired, it is obtained by standard methods from the salt, e.g.,dissolution in water, acidification, extraction into a solvent such asethyl acetate, and stripping the solvent away.

Other pharmaceutically-acceptable cationic salts of the presentinvention are also readily prepared by standard methods. For example, anequivalent of the corresponding cationic hydroxide, carbonate orbicarbonate, or of an amine, is combined with the carboxylic acid in anorganic or aqueous solvent, preferably at reduced temperature (e.g,,0°-5° C.), with vigorous agitation and slow addition of the base. Thesalt is isolated by concentration and/or the addition of a non-solvent.Alternatively, other cationic salts are isolated directly fromhydrogenolysis reaction mixtures by replacing the above sodiumbicarbonate with an equivalent amount of the appropriate base.

Likewise pharmaceutically-acceptable acid addition salts of the presentinvention are readily prepared by standard methods. For example, anequivalent of the acid is combined with the free amine form of thecompound in an organic or aqueous organic solvent. The salt is isolatedby concentration and/or the addition of a non-solvent. As noted abovefor the sodium salt, the acid addition salts are alternatively isolateddirectly from hydrogenolysis reaction mixtures, i.e., without isolationof the free amine, otherwise using similar techniques.

The compounds of the formula (I) wherein R represents an in vivohydrolyzable ester are prepared from the corresponding free acids orcationic salts according to known method, readily identified by thoseskilled in the penicillin art (see for example U.S. Pat. Nos. 3,951,954,4,234,579; 4,287,181; 4,342,693; 4,452,796; 4,342,693; 4,348,264;4,416,891; and 4,457,924). A preferred method of preparation isexemplified below. If desired, an ester containing a basic amine orcarboxylic acid function is converted to an acid addition salt orcationic salt, respectively, according to the methods of the immediatelypreceding paragraphs.

Conjugate diesters of the above formula (I) wherein R is an acylmethylor 1-acylethyl radical derived from a conventional penicillin areconveniently made from a salt (preferably the tetrabutylammonium salt)of the corresponding compound of the formula (I) wherein R is hydrogen,and the halomethyl ester (preferably the iodomethyl ester) of thepenicillin, in protected form when the penicillin contains primary orsecondary amino or carboxylic acid functionality. The preferredprotecting groups are those removed by hydrogenolysis, particularly thebenzyloxycarbonyl group removed by hydrogenolysis under the conditionsdetailed above. Alternatively, azido groups are used in place of thedesired amino groups in the precursor penicillin moiety. The azido groupis hydrogenated to the amino group under those same conditions.Exemplary is the preparative route for compounds of the formula (I)wherein R is in the form of the preferred radical of the formula (A)defined above. If not already in hand, the requisiteN-benzyloxycarbonyl, ampicillin or azidocillin is first converted to itsidomethyl ester by known methods. The latter is in turn reacted with acationic salt of the compound (I) wherein R is hydrogen. (Alternativelythe same intermediate is formed by reaction of the idomethyl ester ofone of the present compounds with the salt of the penicillin). In thefinal step the benzyloxycarbonyl amino or azido group is hydrogenated toan amino group, as noted above.

As indicated above, some of the compounds of the formula (I), generallythose wherein R is hydrogen, have in vitro antibacterial activity. Suchactivity is demonstrated by measuring the minimum inhibitoryconcentrations (MIC's) in mcg/ml against a variety of microorganisms.The procedure which is followed is the one recommended by theInternational Collaborative Study on Antibiotic Sensitivity Testing(Ericcson and Sherris, Acta Pathologica et Microbiologia Scandinav,Suppl. 217, Section B: 64-68 ([1971)], and employs brain heart infusion(BHI) agar and an inocula replicating device. Overnight growth tubes arediluted 100 fold for use as the standard inoculum (20,000-10,000 cellsin approximately 0.002 ml. are placed on the agar surface; 20 ml. of BHIagar/dish). Twelve 2 fold dilutions of the test compound are employed,with initial concentration of the test drug being 200 mcg/ml. Singlecolonies are disregarded when reading plates after 18 hours at 37° C.The susceptibility (MIC) of the test organism is accepted as the lowestconcentration of compound capable of producing complete inhibition ofgrowth as judged by the naked eye.

Those compounds of the formula (I) having said in vitro antibacterialactivity are thus useful as industrial antimicrobials, for example inwater treatment, slime control, paint preservation and woodpreservation, as well as for topical application in mammals. In the caseof use of these compounds for topical application, it is oftenconvenient to admix the active ingredient with a non-toxic carrier, suchas vegetable or mineral oil or an emollient cream. Similarly, it can bedissolved or dispersed in liquid diluents or solvents such as water,alkanols, glycols or mixtures thereof. In most instances it isappropriate to employ concentrations of the active ingredient of fromabout 0.1 percent to about 10 percent by weight, based on totalcomposition.

As also indicated above, the compounds of the formula (I) are generallyof sufficient antibacterial activity to be useful as systemicantibacterial agents, particularly when the sidechain is in thepreferred S-configuration. In determining such in vivo activity, acuteexperimental infections are produced in mice by the intraperitonealinoculation of the mice with a standardized culture of the test organismsuspended in 5 percent hog gastric mucin. Infection severity isstandardized so that the mice receive a lethal dose of the organism (thelethal dose is the minimum inoculum of organism required to consistentlykill 100 percent of the infected, non-treated control mice). The testcompound of the formula (I) is administered at various dosage levels,p.o. or i.p., to groups of infected mice. At the end of the test, theactivity of the mixture is assessed by counting the number of survivorsamong treated animals at a given dose. Activity is expressed as thepercentage of animals which survive at a given dose, or calculated asPD₅₀ (dose which protects 50% of the animals from infection).

Even more generally, the compounds of the formula (I) are of specialvalue as potent inhibitors of microbial beta-lactamases. By thismechanism they increase their own antibacterial effectiveness or theantibacterial effectiveness of a conventional beta-lactam antibiotic(penicillin or cephalosporin) against many microorganisms, particularlythose which produce a beta-lactamase. Thus the ability of the saidcompounds of the formula (I) in vitro is also evaluated by the abilityof the compounds (I) wherein R is H to inhibit the hydrolysis of certainbeta-lactam antibiotics by beta-lactamase enzymes. For example, thehydrolysis of ampicillin and penicillin G is determined by themicroiodometric method of Novick (Biochem. j. 83, 236 (1962)], whilecephaloridine hydrolysis is measured by following the decrease inultraviolet absorbance at 255 nm [O'Callaghan et al., Antimicrob. AgentsChemother. 1968, pp. 57-63 (1969)]. Conditions for both assays areidentical: 0.5M potassium phosphate, pH 6.5 and 37° C. Reactions areinitiated by the addition of the cell-free beta-lactamase, except in thecase of preincubation experiments in which the inhibitor and enzyme areincubated together in the assay mixture for 10 minutes before initiationof the reaction by addition of substrate. With the cell-free extracts ofStaphylococcus aureus, Escherichia coli, Klebsiella pneumoniae andPseudomonas aeruginosa, the substrate is ampicillin at 33 micro M (13microg./ml.). Typical specific activities of the beta-lactamasepreparations are, respectively, 6,019, 88,970, 260 and 76 micromol/hr.per mg. of protein. Penicillin G (33 micromol) is the substrate usedwith the Enterobacter cloacae beta-lactamase, which shows a typicalspecific activity of 10,080 micromol/hr. per mg. of protein.

Cell-free extracts are prepared by sonic treatment (using three 30-sbursts at 4° C. except for S. aureus, which is broken with a Frenchpress) of cultures grown in brain heart infusion on a rotary shakerincubator. For the S. aureus, P. aeruginosa, and E. cloacae strains, denovo synthesis of beta-lactamase is induced by growing a log-phaseculture in the presence of a sublethal concentration of penicillin G at100, 1,000, and 300 microg./ml., respectively, for 2.5 hours.

The ability of compounds of the formula (I) to increase theeffectiveness of a beta-lactam antibiotic can be appreciated byreference to experiments in which the MIC values of the antibioticalone, and a compound of the formula (I) (having R as hydrogen) alone,are determined. These MIC's are then compared with the MIC valuesobtained with a combination of the given antibiotic and the compound ofthe formula (I), wherein R is hydrogen. When the antibacterial potencyof the combination is significantly greater than would have beenpredicted from the potencies of the individual compounds, this isconsidered to constitute synergism or enhancement of activity. The MICvalues of combination are measured using the method described by Barryand Sabath in "Manual of Clinical Microbiology", edited by Lenette,Spaulding and Truant, 2nd Edition, 1974, American Society forMicrobiology.

The compounds of the formula (I) also generally enhance theantibacterial effectiveness of beta-lactam antibiotics in vivo. That is,they lower the amount of the antibiotic which is needed to protect miceagainst an otherwise lethal inoculum of certain beta-lactamase producingbacteria. Such in vivo tests are carried out in the manner describedabove for single agents, but in this case the mice are dosed with acombination of the test compound (I) wherein R is hydrogen or an in vivohydrolzable ester and the beta-lactam antibiotic under study.

In determining whether a particular strain of bacteria is sensitive to aparticular compound of the formula (I) wherein R is an acyloxymethylgroup derived from a beta-lactam antibiotic, it is not necessary tocarry out an in vivo test. Instead, the MIC of a 1:1 molar mixture of acompound of the formula (I) wherein R is hydrogen, and the appropriatebeta-lactam antibiotic is measured according to methods described above.

The ability of the compounds of formula (I), wherein R is hydrogen or ain vivo hydrolyzable ester, to enhance the effectiveness of abeta-lactam antibiotic against beta-lactamase producing bacteria makesthem valuable for co-administration with beta-lactam antibiotics in thetreatment of bacterial infections in mammals, particularly man. In thetreatment of a bacterial infection, the compound of the formula (I) canbe comingled with the beta-lactam antiobiotic, and the two agentsthereby administered simultaneously. Alternatively, the compound of theformula (I) can be administered as a separate agent during a course oftreatment with a beta-lactam antibiotic. In some instances it will beadvantageous to pre-dose the subject with the compound of the formula(I) before initiating treatment with a beta-lactam antibiotic.

When simultaneously administering a compound of formula (I) and abeta-lactam antibiotic, it is preferred to administer a mixture of (I)and the beta-lactam antibiotic in a single formulation. Such apharmaceutical composition will normally comprise the beta-lactamantibiotic, the compound of formula (I) and from about 5 to about 80percent of a pharmaceutically acceptable carrier or diluent by weight.Said carrier or diluent is chosen on the basis of the intended mode ofadministration. For oral administration, tablets, capsules, lozenges,troches, powders, syrups, elixirs, aqueous solutions and suspensions,and the like are used, in accordance with standard pharmaceuticalpractice. The proportional ratio of active ingredient to carrier willnaturally depend on the chemical nature, solubility and stability of theactive ingredient, as well as the dosage contemplated. In the case oftablets for oral use, carriers which are commonly used include lactose,sodium citrate and salts of phosphoric acid. Various disintegrants suchas starch, and lubricating agents, such as magnesium stearate, sodiumlauryl sulfate and talc, are commonly used in tablets. For oraladministration in capsule form, useful diluents are lactose and highmolecular weight polyethylene glycols, e.g. polyethylene glycols havingmolecular weights of from 2000 to 4000. When aqueous suspensions arerequired for oral use, the active ingredient is combined withemulsifying or suspending agents. If desired, certain sweetening and/orflavoring agents can be added. For parenteral administration, whichincludes intramuscular, intraperitoneal, subcutaneous, and intravenousinjection, sterile solutions of the active ingredient are usuallyprepared, and the pH of the solutions are suitably adjusted andbuffered. For intravenous use, the total concentration of solutes shouldbe controlled to render the preparation isotonic. When dosed separately,compounds of the formula (I) are formulated in like manner.

When using the compounds of formula (I) in combination with anotherbeta-lactam antibiotic, said compounds are administered orally orparenterally, i.e., intramuscularly, subcutaneously orintraperitoneally. Although the prescribing physician will ultimatelydecide the dosage to be used in a human subject, the ratio of the dailydosages of the compounds of formula (I) and the beta-lactam antibioticwill normally be in the range from about 1:10 to 3:1 by weight.Additionally, when using the compounds of formula (I) in combinationwith another beta-lactam antibiotic, the daily oral dosage of eachcomponent will normally be in the range from about 10 to about 200 mg.per kilogram of body weight and the daily parenteral dosage of eachcomponent will normally be about 5 to about 50 mg. per kilogram of bodyweight. These daily doses will usually be divided. In some instances,the prescribing physician will determine that dosage outside theselimits are necessary.

As will be appreciated by one skilled in the art, some beta-lactamcompounds are effective when administered orally or parenterally, whileothers are effective only when administered by the parenteral route.When a compound of formula (I) is to be used simultaneously (i.e.comingled) with a beta-lactam antibiotic which is effective only onparenteral administration, a combination formulation suitable forparenteral use will be required. When a compound of formula (I) is to beused simultaneously (comingled) with a beta-lactam antibiotic which iseffective orally or parenterally, combination suitable for either oralor parenteral administration can be prepared. Additionally, it ispossible to administer preparations of the compounds of formula (I)orally, while at the same time administering a further beta-lactamantibiotic parenterally, and it is also possible to administerpreparation of the compounds of formula (I) parenterally, while at thesame time administering the further beta-lactam antibiotic orally.

It is the capacity of compounds of the formula (I), wherein R is anacyloxymethyl derivative of a beta-lactam antibiotic, to hydrolyze andprovide both the compounds of the formula (I) wherein R is hydrogen andthe beta-lactam antibiotic which enhances the activity and broadens theantibacterial spectrum of these compounds relative to the use of anequivalent amount of beta-lactam antibiotic alone.

When using one of the present antibacterial compounds of the formula (I)alone for control of bacterial infections in a mammal, particularly man,the compound is administered alone, or mixed with pharmaceuticallyacceptable carriers or diluents, in the manner described above.

When using the more active compounds of the formula (I) alone to controlbacterial infections, the daily dosage will be similar to those of otherclinically useful beta-lactam antibiotics. Although the prescribingphysician will ultimately decide the dosage to be used in a humansubject, these compounds will normally be used orally at dosages in therange from about 20 to about 100 mg. per kilogram of body weight perday, and parenterally at dosages from about 10 to about 100 mg. perkilogram of body weight per day, usually in divided doses. In someinstances, the prescribing physician will determine that dosages outsidethese limits are needed.

The present invention is illustrated by the following examples. However,it should be understood that the invention is not limited to thespecific details of these examples. Abbreviations are used as follows:THF for tetrahydrofuran; AIBN for azo-bisisobutyronitrile; DMAP for4-dimethylaminopyridine; DMF for dimethylformamide; DMSO fordimethylsulfoxide; tlc for thin-layer chromatography on silica gelplates, with detection by u.v. and/or KMnO₄ spray; ¹ H-nmr for protonnuclear magnetic resonance spectra, with delta in ppm at 60 MHz, unlessotherwise specified. Unless otherwise specified, all operations werecarried out at ambient temperature, generally between 17.5° and 26.5°C.; specified temperatures are in °C.; and all solvents were stripped invacuo.

METHOD A--GRIGNARD REACTIONS EXAMPLE A1 Benzyl6-Bromo-6-[R-1-(N,N-dimethylcarbamoyl)-1-hydroxymethyl]penicillanate

Benzyl 6,6-dibromopenicillanate (72.7 g., 0.162 mol) was dissolved in475 ml. THF and cooled to -78°. Methylmagnesium bromide (59 ml. of 3M inether, 0.178 mol) was added over 3 minutes and the solution stirred 30minutes at -78°. Freshly prepared N,N-dimethylglyoxylamide (18 g., 0.178mol) in 75 ml. THF at -78° was then added in one portion. After stirring5 minutes, the mixture was quenched with acetic acid (26 ml., 0.445mol), warmed and stripped. The residue was taken up in 40 ml. ethylacetate and 500 ml. H₂ O. The organic layer was separated, washed 3×500ml. fresh H₂ O and 1× with brine, dried over Na₂ SO₄, stripped to an oil(84 g.), and chromatographed on 800 g. silica gel with 3:7 ethylacetate:CHCl₃ is eluant, monitoring by tlc, and collecting 500 ml.fractions. Fractions 6 and 7 were stripped to yield 5.3 g. of purifiedtitle product. Fractions 3-5 were stripped to a mixture which wasrechromatographed in like manner to yield an additional 5 g. of purifiedtitle product; tlc Rf 0.4 (3:7 ethyl acetate:CHCl₃); ¹ H-nmr (CDCl₃)delta (ppm) 1.35 (3H, s), 1.61 (3H, s), 2.94 (3H, s), 3.05 (3H, s), 4.46(1H, s), 4.98 (1H, br.s), 5.12 (2H, s), 5.84 (1H, s), 7.37 (5H, s).

EXAMPLE A2 Benzyl6-Bromo-6-[1-(N-isopropylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of the preceding Example, benzyl 6,6-dibromopenicillanate(12.2 g., 0.027 mol) and N-isopropylglyoxylamide (3.8 g., 0.033 mol)were converted to crude title product (16 g.) as an oil. The latter wastaken up in minimal CHCl₃, flakey solids (0.5 g.,) removed by filtrationand the filtrate chromatographed on 600 g. of silica gel using 3:17ethyl acetate:CHCl₃ as eluant to yield purified title product, 0.65 g.,which appeared to be predominantly one isomer; ¹ H-nmr (CDCl₃) delta(ppm) 1.17 (6H, d), 1.35 (3H, s), 1.61 (3H, s), 3.7-4.3 (2H, complex),4.46 (1H, s), 4.62 (1H, s), 5.13 (2H, s), 5.80 (1H, s), 6.52 (1H, br.d),7.3 (5H, s).

EXAMPLE A3 Benzyl6-Bromo-6-[1-(pyrrolidinocarbonyl)-1-hydroxymethyl]penicillanate

By the method of Example A1, chromatographing on 550 g. silica gel with1:4 ethyl acetate:CHCl₃ as eluant and collecting 25 ml. fractions,benzyl 6,6-dibromopenicillanate (41.9 g., 0.093 mol) andN-glyoxyloylpyrrolidine (11.87 g., 0.093 mol) were converted to titleproduct, isolated by combining and stripping fractions 76-100, 4.9 g.; ¹H-nmr (CDCl₃) delta (ppm) 1.39 (3H, s), 1.64 (3H, s), 1.7-2.1 (4H,complex), 3.3-3.8 (4H, complex), 4.53 (1H, s), 4.87 (1H, br.s), 5.18(2H, s), 5.99 (1H, s), 7.36 (5H, s).

EXAMPLE A4 Benzyl6-Bromo-6-[R-1-(piperidinocarbonyl)-1-hydroxymethyl]penicillanate

By the method of Example A1, chromatographing on 600 g. silica gel with1:9 ethyl acetate:CHCl₃ as eluant and collecting 25 ml. fractions,benzyl 6,6-dibromopenicillante (27 g., 0.06 mol) andN-glyoxyloxylpiperidine (13.74 g.) were converted to title productisolated by stripping combined fractions 45-70, 8.0 g.; ¹ H-nmr (CDCl₃)delta (ppm) 1.38 (3H, s), 1.3-1.8 (9H, complex), 3.3-3.8 (4H, complex),4.51 (1H, s), 5.11 (1H, s), 5.18 (2H, s), 5.81 (1H, s), 7.33 (5H, s).

EXAMPLE A5 Benzyl6-Bromo-6-[1-(morpholinocarbonyl)-1-hydroxymethyl]penicillanate

By the method of Example A1, benzyl 6,6-dibromopenicillanate (18 g.,0.040 mol) and N-glyoxyloylmorpholine (4.74 g.) were converted to titleproduct, chromatographed on 250 g., silica gel eluted with 3:7 ethylacetate:CHCl₃. Those fractions containing mainly mp isomer werecombined, 4.54 g.; tlc Rf 0.4 (3:7 ethyl acetate:CHCl₃); ¹ H-nmr (CDCl₃)delta (ppm) 1.40 (3H, s), 1.65 (3H, s), 3.4-3.8 (8H, complex), 4.56 (1H,s), 5.03 (1H, br.s), 5.11 (2H, s), 5.90 (1H, s), 7.38 (5H, s).

PREPARATION A1 Benzyl 6-Bromo-6-[R- andS-1-(allyloxycarbonyl)-1-hydroxymethyl]penicillanate

Benzyl 6,6-dibromopenicillanate (128.9 g., 0.28 mol) was dissolved in500 ml. dry THF and cooled to -78° C. Methylmagnesium bromide (98.9 ml.of 2.9M in ether) was added and the cold mixture stirred for 15 minutes.Allyl glyoxalate (37 g., 0.32 mol) was added in one portion and themixture stirred 1 hour at -78°; quenched with acetic acid (34.4 ml.,0.57 mol), warmed and stripped. The residue was distributed between 500ml. ethyl acetate and 200 ml. H₂ O, and the organic layer separated,washed with 2×100 ml. fresh H₂ O and 1×200 ml. brine, dried over Na₂SO₄, stripped to an oil and chromatographed on 1200 g. of silica gelwith 1:19 ethyl acetate:CHCl₃ as eluant. After the initial 1.5 l. ofeluate was discarded, 20 ml. fractions were collected. Fractions 21-40gave benzyl 6-bromopenicillanate, and fractions 41-60 gave 40 g. of amixture of said 6-bromopenicillanate and title R- and S-isomers.Fractions 61-140 gave 56 g. of residue which was slurried in 100 ml. ofether and filtered to yield crystalline, more polar S-isomer of titleproduct, of unspecified stereochemistry of C.6, 12.3 g.; mp 123°-125°C.; ¹ H-nmr (CDCl₃) delta (300 MHz) 1.38 (3H, s), 1.63 (3H, s), 4.53(1H, s), 4.56-4.76 (3H, complex), 5.17 (2H, s), 5.22-5.36 (3H, complex),5.63 (1H, s), 5.82 (1H, m), 7.34 (5H, s).

The 40 g. mixture from above fractions 41-60 was rechromatographed on1200 g. of silica gel with CHCl₃ as eluant. After discarding theintitial 2 l. of eluate, 20 ml. fractions were collected. Fractions10-60 gave an additional 30 g. of benzyl 6-bromopenicillanate; fractions120-250 gave less polar title R-isomer, 23.6 g.; mp 78°-79° C.; ¹ H-nmr(CDCl₃) delta (300 MHz) 1.37 (3H, s), 1.60 (3H, s), 4.52 (1H, s),4.64-4.72 (3H, complex), 5.15 (2H, ABq), 5.26 (1H, dd, J(1 g)=10 Hz),5.36 (1H, dd, J(1 g)=16 Hz), 5.56 (1H, s), 5.88 (1H, m), 7.32 (5H, s);fractions 251-450 were combined, stripped and the residue slurried in100 ml. ether to yield additional S-isomer, 17 g., identical with thematerial isolated from the initial chromatography.

DEBROMINATION REACTIONS EXAMPLE B1 Benzyl6-beta-[S-1-(Dimethylcarbamoyl)-1-hydroxymethyl]penicillanate

R-Title product of Example A1 (5 g., 0.011 mol) was dissolved in 50 ml.benzene. Tributyltin hydride (9.1 ml., 9.8 g., 0.033 mol) was added andthe mixture refluxed for 2.5 hours, stripped of solvent and the residuetaken up in 100 ml. CH₃ CN and hexane. The CH₃ CN layer was separated,washed 2×75 ml. fresh hexane, stripped to an oil, crystallized fromether, cooled to 0° and title product recovered by filtration, 1.1 g.; ¹H-nmr (CDCl₃) delta (TMS): 1.37 (3H, s), 1.61 (3H, s), 2.94 (3H, s),3.16 (3H, s), 3.53 (1H, d, J=6 Hz), 4.00 (1H, dd, J=4 Hz, 9 Hz), 4.43(1H, s), 4.83 (1H, dd, J=6 Hz, 9 Hz), 5.16 (2H, s), 5.46 (1H, d, J=4Hz), 7.3 (5H, s).

EXAMPLE B2 Benzyl 6-beta-[R- andS-1-(Isopropylcarbamoyl)-1-hydroxymethyl]penicillanate

Title product of Example A2 (mixed R- and S-isomers; 0.65 g., 1.34mmol), was debrominated and crude product isolated as an oil (0.70 g.)from hexane washed acetonitrile according to Example B1. The crudeproduct was chromatographed on 25 g. silica gel using 1:9 ethylacetate:CHCl₃ as eluant, collecting 7 ml. fractions. Fractions 12-18were stripped to yield title product R-epimer, 210 mg.; ¹ H-nmr (CDCl₃)delta (TMS) : 1.20 (6H, d, J=6 Hz), 1.40 (3H, s), 1.65 (3H, s), 3.63(1H, dd, J=4 Hz, 10 Hz), 3.8-4.5 (3H, complex overlapping multiplets),4.41 (1H, s), 5.14 (2H, s), 5.38 (1H, d, J=4 Hz), 7.3 (5H, s). Fractions24-48 were stripped to yield S-epimer, 25 mg.; ¹ H-nmr (CDCl₃ ) delta(TMS): 1.15 (6H, d, J=7 Hz), 1.40 (3H, s), 1.64 (3H, s), 3.57 (1H, d,J=3 Hz), 3.83 (1H, dd, J=4 Hz, 9 Hz), 4.18 (1H, m), 4.44 (1H, s), 4.64(1H, dd, J=3 Hz, 9 Hz, 5.20 (2H, s), 5.51 (1H, d, J=4 Hz), 7.35 (5H, s).

EXAMPLE B3 Benzyl 6-beta-[R- andS-1-(Pyrrolidinocarbonyl)-1-hydroxymethyl]penicillanate

Title product of Example A3 (4.9 g., 9.9 mmol) was debrominatedaccording to Example B1 to yield crude title product as an oil (4.0 g.)from the hexane washed CH₃ CN. The oil was chromatographed on 300 g.silica gel with 1:3 ethyl acetate:CHCl₃ as eluant, collecting 5 ml.fractions and monitoring by tlc. More polar fractions 140-200 werecombined and stripped to yield purified S title product as a second oil,1.5 g. Addition of ethyl acetate gave crystalline S title product, 0.40g., m.p. 88°-92°. Stripping of the ethyl acetate filtrate and treatmentwith ether gave a second crop thereof, 0.50 g., m.p. 90°-93°; tlc Rf 0.3(3:7 ethyl acetate:CHCl₃); ¹ H-nmr (CDCl₃) delta (TMS): 1.38 (3H, s),1.63 (3H, s), 1.92 (4H, m), 3.3-3.8 (5H, complex multiplet), 4.02 (1H,dd, J=4 Hz, 10 Hz), 4.42 (1H, s), 4.70 (1H, br.d.), 5.14 (2H, s), 5.44(1H, d, J=4 Hz), 7.3 (5H, s). Less polar fractions 66-85 were strippedto yield the R-epimer as an oil (1.0 g.), crystallized with ether, 0.37g.; m.p. 88°-90°; tlc Rf 0.45 (3:7 ethyl acetate:CHCl₃). Centerfractions gave a mixture of R- and S-epimers, 1.15 g., suitable forchromatographic recycling.

EXAMPLE B4 Benzyl6-beta-[S-1-(Piperidinocarbonyl)-1-hydroxymethyl]penicillanate

Using a reflux time of 6.5 hours the procedure of the preceding Examplewas used to convert title product of Example A4 (8 g., 0.016 mol) topresent chromatographed title product; 3.6 g.; tlc Rf 0.15 (1:1 ethylacetate:CHCl₃), ¹ H-nmr (CDCl₃) delta (TMS): 1.33 (3H, s), 1.2-1.7 (9H,complex overlapping multiplets), 3.1-3.6 (4H, complex overlappingmulitplets), 3.93 (1H, dd, J=4 Hz, 10 Hz), 4.41 (1H, s), 4.5-4.9 (2H,overlapping multiplets), 5.13 (2H, s), 5.41 (1H, d, J=4 Hz), 7.3 (5H,s).

EXAMPLE B5 Benzyl 6-beta-[R- andS-1-(Morpholinocarbonyl)-1-hydroxymethyl]penicillanate

Using the procedure of Example B3, title product of Example A5 (4.62 g.,0.0086 mol) was converted to mixed title products as an oil (6.0 g.).The latter was chromatographed on 240 g. of silica gel with 3:7 ethylacetate:CHCl₃ as eluant with 10 ml. fractions. Fractions 59-72 werecombined and stripped to yield the less polar R-epimer of title product,an oil which partially crystallized on standing at 5° and was completelycrystallized from ethyl acetate and ether, 0.12 g.; ¹ H-nmr (CDCl₃)delta (TMS): 1.40 (3H, s), 1.64 (3H, s), 3.4-4.0 (10, complexoverlapping multiplets), 4.40 (1H, s), 4.81 (1H, dd, J=8 Hz, 10 Hz),5.16 (2H, s), 5.46 (1H, d, J=4 Hz), 7.35 (5H, s). Fractions, 90-119 werecombined and stripped to yield the more polar S-epimer of title product,1.3 g.; ¹ H-nmr (CDCl₃) delta (TMS): 1.38 (3H, s), 1.61 (3H, s), 3.2-3.9(9H, complex overlapping multiplets), 4.03 (1H, dd, J=4 Hz, 8 Hz), 4.43(1H, s), 4.83 (1H, dd, J=6 Hz, 8 Hz), 5.17 (2H, br.s.), 5.46 (1H, d, J=4Hz), 7.3 (5H, s).

PREPARATION B1 Benzyl6-beta-[S-1-(Allyloxycarbonyl)-1-hydroxymethyl]penicillanate

R-Title product of Preparation A1 (16.3 g.; 0.00337 mol) dissolved in200 ml. benzene was purged with N₂ for 15 minutes. Tributyltin hydride(17.6 ml. of 3.826N in benzene, 0.0673 mol) was then added and themixture refluxed 18 hours, stripped of solvent and partioned in 100 ml.CH₃ CN and 100 ml hexane. The CH₃ CN layer was separated, stripped to anoil and instant title product crystallized by stirring with 100 ml.ether, 6.5 g.; mp 108°-110°; ¹ H-nmr (CDCl₃) delta (300 MHz): 1.46 (3H,s), 1.71 (3H, s), 3.13 (1H, d, J=3 Hz), 3.92 (1H, dd, J=4 Hz, 10 Hz),4.59 (1H, s), 4.77 (2H, d), 4.85 (1H, dd, J=3 Hz, 10 Hz), 5.26 (2H, s),5.37 (1H, d), 5.43 (1H, d), 5.55 (1H, d, J=4 Hz), 5.96 (1H, complex),7.44 (5H, s).

The present preparation was repeated on 21 g. of R-title product ofPreparation A1, using a reflux time of 1 hour. The residual oilfollowing acetonitrile strip was chromatographed on 800 g. of silica gelwith 1:19 ethyl acetate:CHCl₃ as eluant. After discarding the initialliter of eluate, 20 ml. fractions were collected. Fractions 131-190 werestripped to an oil which was crystallized from 100 ml. of ether, 5.8 g.;m.p. 108°-110° C.; structure and stereochemistry confirmed by X-raycrystallographic analysis.

PREPARATION B2 Benzyl6-beta-[R-1-(Allyloxycarbonyl)-1-hydroxymethyl]penicillanate

S-Title product of Preparation A1 (10.1 g., 0.0208 mol), by theprocedure of the preceding Preparation, was converted to instant titleproduct. The initially obtained oil was chromatographed on 400 g., ofsilica gel, eluting with CHCl₃. After 1.5 l. forerun, 20 ml. fractionswere collected. Fractions 48-75 were combined and stripped to yieldpurified title product still as an oil, 5.5 g.; ¹ H-nmr (CDCl₃) delta(CDCl₃) (300 MHz): 1.43 (3H, s), 1.69 (3H, s), 3.41 (1H, d, J=8 Hz),3.98 (1H, dd, J=4 Hz, 8 Hz), 4.53 (1H, s), 4.75 (3H, complex), 5.23 (2H,s), 5.32 (1H, d), 5.41 (1H, d), 5.50 (1H, d, J=4 Hz), 5.96 (1H,complex), 7.42 (5H, s).

The present preparation was repeated on 17 g. of the S-title product ofPreparation A1 using a reflux time of 4 hours and chromatography on 300g. of silica gel with 1:19 ethyl acetate:CHCl₃ as eluant to yield 14.0g. of present purified title product.

METHOD C AMINOLYSIS REACTIONS EXAMPLE C1 Benzyl6-beta-(S-1-Carbamoyl-1-hydroxymethyl)penicillanate

Title product of Preparation F1 (400 mg., 1.0 mmol) was dissolved in 3.6ml. THF and cooled to -15° with stirring. COCl₂ in CCl₄ (0.7M, 2.2 ml.,1.6 mmol); 0.5 minutes later, diisopropylethylamine in THF (0.57M, 3.6ml., 2.1 mmol); and 2.0 minutes later, conc. NH₄ OH (8.25M, 0.5 ml., 4.1mmol) were added. After stirring 20 minutes at -15°, the reactionmixture was quenched with acetic acid (0.42 ml., 0.43 g., 7.2 mmol) andthen poured into 75 ml. of ethyl acetate and 35 ml. H₂ O. The organicphase was washed 3×35 ml. fresh H₂ O, 1× brine, dried and stripped to anoil (500 mg.) which was chromatographed on 30 g. silica gel employing1:2 ethyl acetate:CHCl₃ as eluant. Clean product fractions werecombined, stripped and crystallized from ethyl acetate and ether, 100mg.; ¹ H-nmr (CDCl₃) delta (TMS): 1.40 (3H, s), 1.63 (3H, s), 3.7-4.0(2H, overlapping multiplets), 4.43 (1H, s), 4.65 (1H, m), 5.16 (2H, s),5.46 (1H, d, J=4 Hz), 5.77 (1H, br.), 6.62 (1H, br.), 7.32 (5H, s).

EXAMPLE C2 Benzyl6-beta-[S-1-(Benzylcarbamoyl)-1-hydroxymethyl]penicillanate

Title product of Preparation F1 (0.5 g., 0.0013 mol) was dissolved in 5ml. THF. COCl₂ in CCl₄ (1.2M, 10 ml., 0.012 ml.) was added. Afterstirring 5 minutes, the mixture was stripped to yield the cyclicanhydride, benzyl 6-beta-(1,3-dioxolane-2,5-dion-4-yl)penicillanate as asolid foam. The latter was dissolved in 5 ml. fresh THF and a solutionof benzylamine (0.14 ml., 0.0013 mol) in 1 ml. CH₂ Cl₂ added, forming animmediate precipitate. The reaction mixture was diluted with 10 ml. CH₂Cl₂ and stirred 5 minutes. An additional portion of benzylamine (0.14ml.) was added, stirring continued 10 minutes longer, and the reactionmixture stripped. The residue was distributed between 30 ml. ethylacetate and 30 ml. H₂ O. The pH was adjusted to 6.0 with dilute HCl andthe organic layer was separated washed 2×20 ml. fresh H.sub. 2 O, 1×20ml. brine, dried, stripped to an oil, chromatographed on 40 g. silicagel with 3:7 ethyl acetate:CHCl₃ as eluant, collecting 10 ml. fractions.Fraction numbers 6 to 8 were combined, stripped to an oil,rechromatographed on 50 g. fresh silica gel with 3:17 ethylacetate:CHCl₃ as eluant, monitoring by tlc, to yield purified titleproduct, 60 mg.; tlc Rf 0.6 (3:17 ethyl acetate:CHCl₃); ¹ H-nmr (CDCl₃)delta (TMS): 1.37 (3H, s), 1.62 (3H, s), 3.81 (1H, dd, J=4 Hz, 9 Hz),4.38 (2H, m), 4.41 (1H, s), 4.68 (1H, d, 9 Hz), 5.13 (2H, s), 5.46 (1H,d, J=4 Hz), 7.2 (5H, s), 7.3 (5H, s).

EXAMPLE C3 Benzyl6-beta-[S-1-(tert-Butylcarbamoyl)-1-hydroxymethyl]penicillanate

Title product of Preparation F1 (0.5 g., 0.0013 mol) was coupled withtert-butylamine in THF (0.95N, 5.4 ml., 0.0052 mol) according to ExampleC1. Following acetic acid quench, precipitated acetate salts wereremoved by filtration. The filtrate was poured into 75 ml. ethylacetate/35 ml. H₂ O. The pH was 5.0. The organic layer was separated,washed 3×35 ml. H₂ O, dried, and stripped to an oil (0.7 g.). The latterwas chromatographed on 30 g. silica gel using 3:17 ethyl acetate:CHCl₃as eluant, collecting 10 ml. fractions and monitoring by tlc. Fractions12 to 15 were combined and stripped to yield purified title product,0.20 g.; tlc Rf 0.45 (1:4 ethyl acetate:CHCl₃); ¹ H-nmr (CDCl₃) delta(TMS): 1.36 (9H, s), 1.39 (3H, s), 1.63 (3H, s), 3.77 (1H, dd, J=4 Hz, 8Hz), 3.97 (1H, d, J=3 Hz), 4.41 (1H, s), 4.58 (1H, dd, J=3 Hz, 8 Hz),5.16 (2H, s), 5.49 (1H, d, J=4 Hz), 6.55 (1H, br.s), 7.3 (5H, s).

EXAMPLE C4 Benzyl6-beta-[S-1-(Phenylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example C2, title product of Preparation F1 (0.5 g.,0.0013 mol) and a single portion of aniline (0.1175 ml., 0.0013 mol)were converted to instant title product, as an oil, using 1:10 ethylacetate:CHCl₃ as eluant on chromatography, 0.1 g.; ¹ H-nmr (CDCl₃) delta(TMS): 1.40 (3H, s), 1.66 (3H, s), 3.87 (1H, dd, J=4 Hz, 9 Hz), 4.46(1H, s), 4.83 (1H, d, J=9 Hz), 5.17 (2H, s), 5.53 (1H, d, J=4 Hz),7.0-7.6 (10H, arom.), 8.5 (1H, br.s).

EXAMPLE C5 Benzyl6-beta-[S-1-(Diethylcarbamoyl)-1-hydroxymethyl]penicillanate

Using 1:3 ethyl acetate:CHCl₃ as chromatography eluant, the method ofExample C1 was used to convert title product of Preparation F1 (0.4 g.,1 mmole) and diethylamine (4.2 ml. of 0.97M in THF, 4.1 mmol) to instanttitle product, 0.35 g.; ¹ H-nmr (CDCl₃) delta (TMS): 1.03 (3H, t), 1.15(3H, t), 1.27 (3H, s), 1.53 (3H, s), 3.0-3.9 (4H, overlappingmultiplets), 3.95 (1H, dd, J=4 Hz, 10 Hz), 4.34 (1H, s), 4.69 (1H, d,J=10 Hz), 5.06 (2H, s), 5.37 (1H, d, J=4 Hz), 7.25 (5H, s).

EXAMPLE C6 Benzyl6-beta-[S-1-(Perhydroazepinocarbonyl)-1-hydroxymethyl]penicillanate

Using 2:9 ethyl acetate:CHCl₃ as eluant, the procedure of Example C1 wasused to convert title product of Preparation F1 (0.5 g., 0.0013 mol) andperhydroazepine (homopiperidine, 5.8 ml. of 0.89M in THF, 0.0052 mol) toinstant chromatographed title product, 0.33 g., tlc Rf 0.45 (3:7 ethylacetate:CHCl₃); ¹ H-nmr (CDCl₃) delta (TMS): 1.39 (3H, s), 1.2-2.0 (11H,overlapping complex multiplet), 3.0-4.3 (5H, complex overlappingmultiplets), 4.04 (1H, dd, J=4 Hz, 10 Hz), 4.45 (1H, s), 4.81 (1H, d,J=10 Hz), b 5.17 (2H, s), 5.45 (1H, d, J=4 Hz), 7.3 (5H, s).

EXAMPLE C7 Benzyl6-beta-[S-1-Hydroxypiperidinocarbonyl)-1-hydroxymethyl]penicillanate

By the method of Example C1, title product of Preparation F1 (0.45 g.,0.00116 mol) and 4-hydroxypiperidine (0.117 g., 0.00116 mol) wereconverted to instant title product. The crude material was isolated as asolid foam (0.38 g.) which was chromatographed on 50 g. silica gel usingethyl acetate as eluant to yield purified title product as a secondsolid foam, 0.13 g.; tlc Rf 0.3 (ethyl acetate); ¹ H-nmr (CDCl₃) delta(TMS): 1.36 (3H, s), 1.4-2.0 (4H, complex multiplet), 2.9-4.1 (8H,complex overlapping multiplets), 4.40 (1H, s), 4.80 (1H, br.d, J=9 Hz),5.14 (2H, br.s), 5.43 (1H, d, J=4 Hz), 7.3 (5H, s).

EXAMPLE C8 Benzyl6-beta-[S-1-(4-Formylpiperazinocarbonyl)-1-hydroxymethyl]penicillanate

By the procedure of Example C1, adjusting the pH from 3.2 to 5.8 with 2NNaOH during aqueous wash and using 3% methanol in ethyl acetate aseluant, title product of Preparation F1 (0.40 g., 1.0 mmol) andN-formylpiperazine (4.2 ml. of 0.97M in THF, 4.1 mmol) were converted toinstant, chromatographed title product, 0.26 g.; tlc Rf 0.4 (1:19methanol:ethyl acetate); ¹ H-nmr (CDCl₃) delta (TMS): 1.39 (3H, s), 1.60(3H, s), 3.2-4.0 (8H, overlapping multiplets), 4.05 (1H, dd, J=4 Hz, 10Hz), 4.47 (1H, s), 4.90 (1H, br.d), 5.20 (2H, s), 5.53 (1H, d, J=4 Hz),7.35 (5H, s), 8.06 (1H, s).

EXAMPLE C9 Benzyl6-beta-[S-1-(Methylcarbamoyl)-1-hydroxymethyl]penicillanate

By the procedure of Example C1 adjusting the pH from 3.5 to 5.0 duringaqueous wash and using ethyl acetate as eluant, title product ofPreparation F1 (0.40 g., 1 mmol) and methylamine (3.3 ml. of 1.24M, 1.24mmols) were converted to present, chromatographed title product as anoil, 0.37 g.; ¹ H-nmr (CDCl₃) delta (TMS): 1.41 (3H, s), 1.66 (3H, s),2.83 (3H, d, J=5 Hz), 3.85 (1H, dd, J=4 Hz, 9 Hz), 4.33 (1H, br.d), 4.46(1H, s), 4.73 (1H, br. dd), 5.11 (2H, s), 5.54 (1H, d, J=4 Hz), 6.9 (1H,br. multiplet), 7.4 (5H, s).

EXAMPLE C10 Benzyl6-beta-[S-1-(2-Hydroxyethylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example C1, using ethyl acetate as eluant, titleproduct of Preparation F1 (0.40 g., 1.0 mmol) and ethanolamine (2.5 ml.of 1.7M in THF, 4.1 mmols) were converted to instant, chromatographedtitle product as an oil, 0.33 g.; tlc Rf 0.2 (ethyl acetate), 0.6 (1:9methanol:ethyl acetate); ¹ H-nmr (CDCl₃) delta (TMS): 1.40 (3H, s), 1.64(3H, s), 3.2-4.0 (6H, overlapping multiplets), 4.43 (1H, s), 4.5-4.8(2H, overlapping multiplets), 5.16 (2H, s), 5.46 (1H, d, J=4 Hz), 7.35(5H, s).

EXAMPLE C11 Benzyl6-beta-[S-1-(1,2,3,4-Tetrahydroisoquinolinocarbonyl)-1-hydroxymethyl]penicillanate

By the method of Example C9, using 3:17 ethyl acetate:CHCl₃ as eluant,title product of Preparation F1 (0.40 g., 1.0 mmol) and1,2,3,4-tetrahydroisoquinoline (5.1 ml. of 0.8M in THF, 4.1 mmols) wereconverted to instant, chromatographed title product, 0.25 g.; tlc Rf0.55 (3:17 ethyl acetate:CHCl₃); ¹ H-nmr (CDCl₃) delta (TMS): 1.35 (3H,br.s), 1.60 (3H, br.s), 2.7-3.0 (2H, complex multiplets), 3.6-4.2 (5H,overlapping multiplets), 4.44 (1H, s), 4.6-5.0 (3H, overlappingmultiplets), 5.15 (2H, s), 5.47 (1H, d, J=4 Hz), 7.09 (4H, s), 7.3 (5H,s).

EXAMPLE C12 Benzyl6-beta-[S-1-(N-Methyl-N-[2-hydroxyethyl]carbamoyl)-1-hydroxymethyl]penicillanate

By the procedure of Example C1, adjusting the pH from 3.2 to 5.5 duringwater wash and using 3:1 ethyl acetate:CHCl₃ as eluant, title product ofPreparation F1 (0.40 g., 1 mmol) and N-methylethanolamine (3.3 ml. of0.8M in THF, 4.1 mmols) were converted to chromatographed title productas an oil, 0.25 g.; tlc Rf 0.25 (3:1 ethyl acetate:CHCl₃); ¹ H-nmr(CDCl₃) delta (TMS), 300 MHz: 1.37 (3H, br.s), 1.62 (3H, br.s), 2.96(1.5H, s), 3.22 (1.5H, s), 3.4-3.9 (4H, overlapping multiplets), 4.0-4.2(1H, overlapping multiplets), 4.48 (0.5H, s), 4.49 (0.5H, s), 4.85(0.5H, d, J=9 Hz), 4.93 (0.5H, d, J=10 Hz), 5.20 (2H, s), 5.50 (1H, d,J=4 Hz), 7.4 (5H, s), reflecting a 1:1 mixture of amide conformers.

EXAMPLE C13 Benzyl6-beta-[S-1-(2-Acetamidoethylcarbamoyl)-1-hydroxymethyl]penicillanate

By the procedure of Example C6, adjusting the pH from 4.0 to 5.3 duringaqueous wash and 1:19 methanol:ethyl acetate as eluant title product ofPreparation F1 (0.40 g., 1.0 mmol) and N-acetylethylenediamine (0.42 g.,4.1 mmols) in 1 ml. THF were converted to instant, chromatographed titleproduct, 0.20 g.; tlc Rf 0.25 (1:19 methanol:ethyl acetate); ¹ H-nmr(CDCl₃) delta (TMS): 1.40 (3H, s), 1.64 (3H, s), 1.95 (3H, s), 3.4 (4H,overlapping complex), 3.93 (1H, dd, J=4 Hz, 7 Hz), 4.46 (1H, s), 4.65(2H, overlapping multiplets), 5.20 (2H, s), 5.52 (1H, d, J=4 Hz), 6.8(1H, broad s), 7.35 (5H, s).

EXAMPLE C14 Benzyl6-beta-[S-1-(Di(2-hydroxyethyl)carbamoyl)-1-hydroxymethyl]penicillanate

Using 1:19 methanol:ethyl acetate as eluant, but otherwise according tothe procedure of Example C1, title product of Preparation F1 (400 mg.,1.0 mmol) and diethanolamine (4.3 ml. of 1.04M in THF, 4.1 mmols) wereconverted to instant title product, 90 mg.; tlc Rf 0.3 (1:19methanol:ethyl acetate); ¹ H-nmr (CDCl₃) delta (300 MHz): 1.36 (3H, s),1.61 (3H, s), 3.3-3.9 (8H, overlapping multiplets), 4.05 (1H, dd, J=4Hz, 9 Hz), 4.47 (1H, s), 4.91 (1H, d, J=9 Hz), 5.19 (2H, s), 5.49 (1H,d, J=4 Hz), 7.4 (5H, s).

EXAMPLE C15 Benzyl6-beta-[S-1-(Dipropylcarbamoyl)-1-hydroxymethyl]penicillanate

Using 1:10 ethyl acetate:CHCl₃ as eluant, but otherwise according to theprocedure of Example C1, title product of Preparation F1 (280 mg., 0.72mmol) and dipropylamine (3.9 ml. of 0.73M in THF, 1.17 mmoles) wereconverted to instant title product, 110 mg.; ¹ H-nmr (CDCl₃) delta:0.7-1.1 (6H, overlapping triplets), 1.37 (3H, s), 1.62 (3H, s), 1.2-1.9(4H, overlapping multiplets), 3.1-3.5 (4H, overlapping multiplets), 3.79(1H, d, J=7 Hz), 4.03 (1H, dd, J=4 Hz, 10 Hz), 4.43 (1H, s), 4.78 (1H,dd, J=7 Hz, 10 Hz), 5.13 (2H, s), 5.44 (1H, s, J=4 Hz), 7.3 (5H, s).

EXAMPLE C16 Benzyl 6-beta-[S-1-(N-Benzyl-N-methylcarbamoyl)-1-hydroxymethyl]penicillanate

Using 1:10 methanol:ethyl acetate as eluant, but otherwise according toExample C1, title product of Preparation F1 (0.5 g., 1.29 mmols) andN-methylbenzylamine (0.68 ml., 5.17 mmols) were converted to instanttitle product, 0.23 g.; ¹ H-nmr (CDCl₃) delta: 1.37 (3H, br. s), 1.47(1.2H, s), 1.61 (1.8H, s), 2.84 (1.2H, s), 3.00 (1.8H, s), 3.32 (1H,br.d, J=6 Hz), 4.00 (1H, dd, J=4 Hz, 9 Hz), 4.3-4.9 (4H, complex), 5.12(2H, s), 5.45 (1H, d, J=4 Hz), 7.4-7.2 (10H, aromatics), reflectingamide conformers in 2:3 ratio.

EXAMPLE C17 Benzyl6-beta-[S-1-(N-Methyl-N-phenylcarbamoyl)-1-hydroxymethyl]penicillanate

Using 1:4 ethyl acetate:CHCl₃ as eluant, the method of Example C1 wasemployed to convert title product of Preparation F1 (0.5 g., 1.29 mmols)and N-methylaniline (0.56 ml., 5.17 mmols) to instant title product,0.31 g.; ¹ H-nmr (CDCl₃) delta (300 MHz): 1.38 (3H, s), 1.43 (3H, s),3.37 (3H, s), 4.06 (1H, dd, J=4 Hz, 10 Hz), 4.44 (1H, s), 4.58 (1H, d,J=10 Hz), 5.23 (2H, s), 5.37 (1H, d, J=4 Hz), 7.3-7.6 (10H, aromatics).

EXAMPLE C18 Benzyl6-beta-[S-1-(N-Benzyl-N-(2-hydroxyethyl)carbamoyl)-1-hydroxymethyl]penicillanate

Using 1:1 ethyl acetate:CHCl₃ as eluant, the procedure of Example C1 wasused to convert title product of Preparation F1 (0.5 g., 1.29 mmols) andN-benzylethanolamine (0.78 g., 5.17 mmols) to instant title product,0.19 g.; ¹ H-nmr (CDCl₃) delta: 1.35 (3H, s), 1.41, (1.5H, s), 1.58(1.5H, s), 3.2-4.3 (7H, complex), 4.36 (0.5H, s), 4.40 (0.5H, s),4.5-4.9 (2H, complex), 5.07 (2H, s), 5.42 (1H, d, J=4 Hz), 7.1-7.3 (10H,aromatics), reflecting an approximately 1:1 mixture of amide conformers.

EXAMPLE C19 Benzyl6-beta-[S-1-(4-Phenylpiperazinocarbonyl)-1-hydroxymethyl]pencillanate

Using 1:10 ethyl acetate:CHCl₃ as eluant and otherwise the method ofExample C1, title product of Preparation F1 (0.4 g., 1 mmol) and4-phenylpiperidine (0.66 g., 4.1 mmols) were converted to instant titleproduct, 0.46 g.; ¹ H-nmr (CDCl₃) delta: 1.38 (3H, br. s), 1.5-2.0 (4H,complex), 2.3-3.4 (4H, complex), 3.7-4.3 (3H, complex), 4.42 (1H, br.s),4.86 (1H, br.d, J=9 Hz), 5.13 (2H, br.s), 5.50 (1H, br.d., J=4 Hz),7.0-7.4 (10H, aromatics).

EXAMPLE C20 Benzyl6-beta-[S-1-(Dibenzylcarbamoyl)-1-hydroxymethyl]penicillanate

Using CHCl₃ as eluant, the method of Example C1 was employed to converttitle product of Preparation F1 (0.4 g., 1 mmol) and dibenzylamine (7.9ml. of 0.52M in THF, 4.1 mmols) title product, 0.53 g.; Rf 0.78 (3:7ethyl acetate:CHCl₃); ¹ H-nmr (CDCl₃) delta: 1.35 (3H, s), 1.43 (3H, s),4.10 (1H, dd, J=4 Hz, 10 Hz), 4.43 (1H, s), 3.8-5.2 (6H, complexoverlapping multiplets), 5.16 (2H, s), 5.54 (1H, d, J=4 Hz), 7.1-7.5(15H, aromatics).

EXAMPLE C21 Benzyl6-beta-[S-1-(L-2-(Hydroxymethyl)pyrrolidinocarbonyl)-1-hydroxymethyl)penicillanate

Using ethyl acetate as eluant, the method of Example C1 was employed toconvert title product of Preparation F1 (0.4 g., 1 mmol) and L-prolinol(0.40 ml., 0.41 g., 4.1 mmols) to instant title product, 0.25 g.; tlc Rf0.2 (ethyl acetate); ¹ H-nmr (CDCl₃) delta: 1.37 (3H, s), 1.63 (3H, s),1.7-2.1 (4H, complex), 3.3-3.8 (4H, complex), 3.8-4.6 (3H, complex),4.46 (1H, s), 4.6-4.9 (2H, complex), 5.17 (2H, s), 5.45 (1H, d, J=4 Hz),7.35 (5H, s).

EXAMPLE C22 Benzyl6-beta-[S-1-(L-2-(Benzyloxycarbonyl)pyrrolidinocarbonyl)-1-hydroxymethyl]penicillanate

The hydrochloride salt of the benzyl ester of L-proline (1 g., 4.1mmols) was dissolved in 7 ml. H₂ O, layered with 10 ml. ethyl acetate,and the pH adjusted from 3.0 to 8.0 with 2N NaOH. The aqueous layer wasseparated and extracted 1×10 ml. fresh ethyl acetate. The organic layerswere combined, dried and stripped to yield the free base form of thebenzyl ester of L-proline (800 mg.).

Using 1:9 ethyl acetate:CHCl₃ as eluant, the method of Example C1 wasused to convert title product of Preparation F1 (0.4 g., 1 mmole) andthe above free base to instant title product, 0.50 g.; tlc Rf 0.3 (1:9ethyl acetate:CHCl₃); ¹ H-nmr (CDCl₃) delta (300 MHz): 1.36 (2.2H, s),1.38 (0.8H, s), 1.61 (0.8H, s), 1.62 (2.2H, s), 1.8-2.3 (4H, complex),3.5-4.0 (3H, complex), 4.01 (0.25H, dd, J=4 Hz, 10 Hz), 4.05 (0.75H, dd,J=4 Hz, 10 Hz), 4.49 (0.25H, s), 4.50 (0.75H, s), 4.5-4.8 (1H, complex),4.87 (0.75H, d, J=10 Hz), 5.18 (0.5H, s), 5.20 (1.5H, s), 5.22 (1.5H,s), 5.23 (0.5H, s), 5.49 (0.75H, d, J=4 Hz), 5.56 (0.25H, d, J=4 Hz),7.3-7.5 (10H, complex), reflecting an amide conformer mixture in about1:3 ratio.

EXAMPLE C23 Benzyl6-beta-[S-1-(N-cyclohexyl-N-methylcarbamoyl)-1-hydroxymethyl]penicillanate

Using 1:4 ethyl acetate as eluant, the method of Example C1 was employedto convert title product of Preparation F1 (0.4 g., 1 mmol) andN-methylcyclohexylamine (0.5 ml., 4.1 mmol) to instant title product, 81mg.; ¹ H-nmr (CDCl₃) delta: 1.36 (3H, s), 1.60 (3H, s), 1.0-2.0 (10H,complex), 2.77 (1.5H, s), 2.94 (1.5H, s), 3.9-4.1 (1H, complex), 4.42(1H, s), 4.5-4.9 (2H, complex), 5.13 (2H, s), 5.43 (1H, d, J=4 Hz), 7.25(5H, s), reflecting amide conformers in about 1:1 ratio.

EXAMPLE C24 Benzyl6-beta-[S-1-(N-Benzyl-N-phenylcarbamoyl)-1-hydroxymethyl]penicillanate

Using ethyl acetate as eluant, the method of Example C1 was used toconvert title product of Preparation F1 (0.4 g., 1 mmol) andN-phenylbenzylamine (0.75 g., 4.1 mmols) to instant title product, 200mg.; tlc Rf 0.6 (3:7 ethyl acetate:CHCl₃); ¹ H-nmr (CDCl₃) delta (300MHz): 1.40 (3H, s), 1.43 (3H, s), 3.20 (1H, d, J=7 Hz), 4.09 (1H, dd,J=4 Hz, 9 Hz), 4.45 (1H, s), 4.56 (1H, dd), 4.97 (2H, s), 5.24 (2H, s),5.43 (1H, d, J=4 Hz), 7.1-7.6 (15H, aromatic complex).

EXAMPLE C25 Benzyl6-beta-[S-1-(N-Benzyl-N-ethylcarbamoyl)-1-hydroxymethyl]penicillanate

Using 1:9 ethyl acetate:CHCl₃ as eluant in the procedure of Example C1,title product of Preparation F1 (0.4 g., 1 mmole) and N-ethylbenzylamine(6.1 ml. of 0.67M in THF, 4.1 mmols) were converted to instant titleproduct, 0.50 g.; Rf 0.25 (1:4 ethyl acetate:CHCl₃); ¹ H-nmr (CDCl₃)delta: 1.06 (1.5H, t), 1.18 (1.5H, t), 1.37 (3H, br.s), 1.45 (1.5H, s),1.60 (1.5H, s), 3.0-3.8 (3H, complex), 3.9-4.2 (1H, complex), 4.6-5.0(4H, complex), 5.17 (2H, s), 5.50 (1H, d, J=4 Hz), 7.2-7.4 (10H,aromatic complex), reflecting amide conformers in about 1:1 ratio.

EXAMPLE C26 Benzyl6-beta-[S-1-(4-Phenylpiperazinocarbonyl)-1-hydroxymethyl]penicillanate

By the procedure of Example C1, using 3:7 ethyl acetate:CHCl₃ as eluant,title product of Preparation F1 (0.4 g., 1.03 mmols) andN-phenylpiperazine (neat, 0.63 ml., 4.13 mmols) were converted toinstant title product as a dry foam, 0.43 g.; tlc Rf 0.4 (3:7 ethylacetate:CHCl₃), ¹ H-nmr (CDCl₃) delta: 1.36 (3H, s), 1.61 (3H, s),3.0-3.9 (8H, complex), 4.02 (1H, dd, J=4 Hz, 9 Hz), 4.43 (1H, s), 4.9(1H, dd), 5.14 (2H, s), 5.46 (1H, d, J=4 Hz), 7.2-7.6 (10H, aromatics).

EXAMPLE C27 Benzyl6-beta-[S-1-(Isoindolinocarbonyl)-1-hydroxymethyl]penicillanate

By the procedure of the preceding Example, title product of PreparationF1 (400 mg., 1.0 mmol) and isoindoline (neat, 0.6 g., 4.1 mmol) wereconverted to instant, chromatographed crystalline title product, finallyrecovered by slurry in a small amount of ether and filtration, 0.258 g.;¹ H-nmr (CDCl₃) delta (300 MHz): 1.40 (3H, s), 1.67 (3H, s), 4.15 (1H,dd, J=4 Hz, 10 Hz), 4.7-5.0 (5H, complex), 5.24 (2H, s), 5.58 (1H, d,J=4 Hz), 7.3-7.5 (9H, aromatics).

EXAMPLE C28 Benzyl6-beta-[S-1-(N-(2-Hydroxyethyl)-N-phenylcarbamoyl)-1-hydroxymethyl]penicillanate

Except that the acetic acid quenched reaction mixture was stripped priorto dilution with ethyl acetate and extraction with water, the procedureof Example C26 was used to convert title product of Preparation F1 (0.37g., 0.956 mmol) and N-(2-hydroxyethyl)aniline (neat, 0.479 ml., 3.824mmol) to instant, chromatographed title product as an oil, 0.13 g.; tlcRf 0.35 (3:7 ethyl acetate:CHCl₃); ¹ H-nmr (CDCl₃) delta 1.36 (3H, s),1.60 (3H, s), 3.3-4.4 (5H, complex), 4.42 (1H, s), 4.6-4.8 (2H,complex), 5.13 (2H, s), 5.35 (1H, d, J=4 Hz), 6.6-7.4 (10H, aromatics).

EXAMPLE C29 Benzyl6-beta-[S-1-(N-(Ethoxycarbonylmethyl)-N-benzylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example C1, title product of Preparation F1 (0.387 g.,1 mmol) and N-benzylglycine ethyl ester (7.7 ml., 4.1 mmol) wereconverted to instant title product, chromatographed using 1:9 ethylacetate:CHCl₃ as eluant, 0.371 g.; tlc Rf 0.5 (3:7 ethyl acetate:CHCl₃);¹ H-nmr (CDCl₃) delta: 1.22 (3H, t), 1.37 (3H, br.s), 1.52 (1.5H, s),1.58 (1.5H, s), 3.2 (1H, br.s), 3.8-4.3 (5H, complex), 4.41 (1H, s), 4.8(2H, complex), 5.12 (2H, s), 5.46 (1H, overlapping doublets), 7.2-7.4(10H, aromatics), representing amide conformers in about 1:1 ratio.

EXAMPLE C30 Benzyl6-beta-[S-1-(N-(Dimethylcarbamoylmethyl)-N-benzylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example C1, employing ethyl acetate as eluant, titleproduct of Example F1 (0.387 g., 1 mmol) and2-benzylamino-N,N-dimethylacetamide (0.8 g., 4.1 mmols) were convertedto instant title product, 0.232 g.; tlc Rf 0.3 (ethyl acetate); ¹ H-nmr(CDCl₃) delta (representing amide conformers in about 3:4 ratio): 1.36(3H, s), 1.53 (1.7H, s), 1.60 (1.3H, s), 2.85 (1.3H, s), 2.90 (4.5H,br.s), 3.8-4.3 (5H, complex), 4.42 (1H, s), 4.6-5.0 (2H, complex), 5.16(2H, s), 5.50 (1H, overlapping doublets), 7.3-7.4 (10H, aromatics).

EXAMPLE C31 Benzyl6-beta-[S-(1-(N-Methyl-N-(4-methylphenyl)carbamoyl)-1-hydroxymethyl]penicillanate

By the method of the Example C1, eluting with 1:4 ethyl acetate:CHCl₃,title product of Preparation F1 (0.8, 2.07 mmols) andN-methyl-p-toluidine (1 g., 8.27 mmols) were converted to instant titleproduct 0.58 g., ¹ H-nmr (CDCl₃) delta (300 MHz): 1.37 (3H, s), 1.45(3H, s), 2.40 (3H, s), 3.30 (3H, s), 4.03 (1H, dd, J=4 Hz, 10 Hz), 4.41(1H, s), 4.56 (1H, overlapping doublets), 5.19 (2H, s), 5.34 (1H, d, J=4Hz), 7.25 (5H, s), 7.40 (4H, s).

EXAMPLE C32 Benzyl6-beta-[S-1-(N-(Methylcarbamoylmethyl)-N-benzylcarbamoyl)-1-hydroxymethyl)penicillanate

By the method of Example C30, title product of Preparation F1 (3.87 g.,1 mmol) and 2-benzylamino-N-methylacetamide (1 g., 5.2 mmols) wereconverted to instant title product, 0.34 g.; ¹ H-nmr (CDCl₃) delta(representing amide conformers in about 1:1 ratio): 1.36 (3H, s), 1.49(1.5H, s), 1.56 (1.5H, s), 2.68 (3H, d), 3.6-4.4 (4H, complex), 4.43(1H, s), 4.6-5.1 (3H, complex), 5.18 (2H, s), 5.52 (1H, overlappingdoublets), 6.4 (1H, complex), 7.2-7.3 (10H, aromatics).

EXAMPLE C33 Benzyl6-beta-[S-1-(N-Methyl-N-(4-methoxyphenyl)carbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example C26, title product of Preparation F1 (0.8 g.,2.07 mmols) and N-methyl-p-anisidine (1.13 g., 8.26 mmols) wereconverted to instant, chromatographed title product, 0.63 g.; ¹ H-nmr(CDCl₃) delta (300 MHz); 1.37 (3H, s), 1.46 (3H, s), 3.29 (3H, s), 3.86(3H, s), 4.02 (1H, dd, J=4 Hz, 10 Hz), 4.41 (1H, s), 4.53 (1H,overlapping doublets), 5.19 (2H, s), 5.35 (1H, d, J=4 Hz), 7.12 (4H,ABq), 7.40 (5H, s).

EXAMPLE C34 Benzyl6-beta-[S-1-(4-(2-Pyridyl)piperazinocarbonyl)-1-hydroxymethyl]penicillanate

By the method of Example C19, title product of Preparation F1 (0.8 g.,2.07 mmols) and N-(2-pyridyl)piperazine (1.35 g., 8.26 mmols) wereconverted to instant, chromatographed title product, 0.5 g.; mp144°-146°; tlc Rf 0.3 (1:1 ethyl acetate:CHCl₃); ¹ H-nmr (CDCl₃) delta:1.37 (3H, s), 1.62 (3H, s), 3.4-3.8 (8H, complex), 4.01 (1H, dd, J=4 Hz,9 Hz), 4.42 (1H, s), 4.97 (1H, d, J=9 Hz), 5.15 (2H, s), 5.46 (1H, d,J=4 Hz), 6.6 (2H, complex), 7.3 (5H, s), 7.5 (1H, complex), 8.15 (1H,complex).

EXAMPLE C35 Benzyl6-beta-[S-1-(Indolinocarbonyl)-1-hydroxymethyl]penicillanate

By the method of Example C26, except to recover a portion of theindoline as a crystalline salt on stripping prior to chromatography,title product of Preparation F1 (0.8 g., 2.07 mmols) and indoline (9.2ml. of 0.89M in THF, 8.2 mmols) were converted to instant,chromatographed title product, 0.100 g.; tlc Rf 0.65 (3:7 ethylacetate:CHCl₃); ¹ H-nmr (CDCl₃) delta (300 MHz): 1.40 (3H, s), 1.67 (3H,s), 3.06 (2H, complex), 4.0-4.5 (4H, complex), 4.56 (1H, s), 4.89 (1H,d, J=9 Hz), 5.24 (2H, s), 5.62 (1H, d, J=4 Hz), 7.0-7.5 (8H, complex),8.19 (1H, d, J=8 Hz).

EXAMPLE C36 Benzyl6-beta-[S-1-(N-(Pyrrolidinocarbonylmethyl)-N-benzylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example C24, title product of Preparation F1 (0.42 g.,1.1 mmols) and N-[2-(benzylamino)acetyl]pyrrolidine (0.95 g., 4.3 mmols)were converted to instant, chromatographed title product, 0.317 g.; tlcRf 0.5 (ethyl acetate); ¹ H-nmr (CDCl₃) delta (300 MHz) (representingthe two amide rotamers in 6:7 ratio): 1.35 (1.6H, s), 1.37 (1.4H, s),1.50 (1.6H, s), 1.60 (1.4H, s), 1.7-2.0 (4H, complex), 3.0-3.5 (4H,complex), 3.69 (0.5H, d, J=17 Hz), 4.0-4.2 (2H, complex), 4.37 (0.5H, d,J=15 Hz), 4.46 (0.54H, s), 4.47 (0.46H, s), 4.67 (0.5H, d, J=17 Hz),4.80 (0.5H, d, J=10 Hz), 4.91 (1H, complex), 5.17 (1.1H, s), 5.18 (0.9H,s), 5.54 (0.54H, d, J=4 Hz), 5.57 (0.46H, d, J=4 Hz), 7.2-7.5 (10H,complex).

EXAMPLE C37 Benzyl6-beta-[S-1-(N-Benzyl-N-isopropylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example C20, title product of Example F1 (0.8 g., 2.06mmols) and N-benzyliospropylamine (0.718 ml., 4.13 mmols) were convertedto instant chromatographed title product, 0.31 g.; ¹ H-nmr (CDCl₃) delta(300 MHz) (reflecting two amide conformers in 5:6 ratio): 1.14 (1.6H, d,J=7 Hz), 1.19 (2.7H, br.d, J=7 Hz), 1.23 (1.6H, d, J=7 Hz), 1.38 (1.4H,s), 1.42 (1.6H, s), 1.44 (1.4H, s), 1.67 (1.6H, s), 2.98 (1H, complex),4.06 (0.45H, dd, J=4 Hz, 9 Hz), 4.11 (0.55H, dd, J=4 Hz, 10 Hz), 4.4(4H, complex), 4.9-5.1 (1H, complex), 5.21 (0.9H, s), 5.23 (1.1H, s),5.49 (0.45H, d, J=4 Hz), 5.55 (0.55H, d, J=4 Hz), 7.2-7.5 (10H,complex).

EXAMPLE C38 Benzyl6-beta-[S-1-(N-(2-(2-Pyridyl)ethyl)-N-methylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example C1, using 1:49 methanol:ethyl acetate aseluant, title product of Example F1 (0.8 g., 2.06 mmols) and2-(2-methylaminoethyl)pyridine (1.14 ml., 4.13 mmols) were converted toinstant title product, 0.7 g.; ¹ H-nmr (CDCl₃) delta (300 MHz)(reflecting two amide conformers in 3:4 ratio): 1.46 (3H, s), 1.62 (3H,s), 2.89 (1.7H, s), 3.08 (1.3H, s), 2.9-3.2 (2H, complex), 3.73 (1.2H,complex), 4.08 (1.8H, complex), 4.47 (0.43H, s), 4.48 (0.57H, s), 4.83(0.43H, d, J=9 Hz), 5.04 (0.57H, d, J=10 Hz), 5.20 (2H, s), 5.48 (0.43H,d, J=4 Hz), 5.52 (0.57H, d, J=4 Hz), 7.1-8.6 (9H, aromatics).

EXAMPLE C39 Benzyl6-beta-[S-1-(N-(Ethoxycarbonylmethyl)-N-methylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example C23, title product of Preparation F1 (0.611 g.,1.6 mmol) and sarcosine ethyl ester (5.5 ml. of 0.57M in THF, 6.3 mmols)were converted to instant, chromatographed title product, 0.59 g.; tlcRf 0.25 (3:7 ethyl acetate:CHCl₃); ¹ H-nmr (CDCl₃) delta (300 MHz)(reflecting the two amide conformers in 3:5 ratio): 1.27 (3H, t), 1.38(3H, br.s), 1.60 (1.1H, s), 1.64 (1.9H, s), 3.00 (1.1H, s), 3.24 (1.9H,s), 3.92 (0.6H, d, J=18 Hz), 4.0-4.4 (5H, complex), 4.46 (0.4H, s), 4.49(0.6H, s), 4.80 (0.4H, d, J=10 Hz), 4.95 (0.6H, d, J=9 Hz), 5.20 (2H,s), 5.51 (0.6H, d, J=4 Hz), 5.55 (0.4H, d, J=4 Hz), 4.4 (5H, s).

EXAMPLE C40 Benzyl6-beta-[S-1-(N-(Pyrrolidinocarbonylmethyl)-N-methylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example C19, title product of Preparation F1 (600 mg.,1.6 mmol) and N-[2-(methylamino)acetyl]pyrrolidine (0.88 g., 6.2 mmols)were converted to instant chromatographed title product, 0.20 g.; tlc Rf0.6 (3:2 ethyl acetate:CHCl₃); ¹ H-nmr (CDCl₃) delta (reflecting the twoamide conformers in 2:1 ratio): 1.35 (3H, s), 1.60 (3H, s), 1.86 (4H,complex), 2.95 (1H, s), 3.22 (2H, s), 3.40 (4H, complex), 3.9-4.3 (3H,complex), 4.40 (0.3H, s), 4.42 (0.7H, s), 4.8 (1H, overlappingdoublets), 5.15 (2H, s), 5.44 (1H, overlapping doublets), 7.3 (5H, s).

EXAMPLE C41 Benzyl6-beta-[S-1-(N,N-bis-(Ethoxycarbonylmethyl)carbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example C23, title product of Example F1 (600 mg., 1.6mmols) and diethyl iminodiacetate (1.2 g., 6.2 mmols) were converted toinstant chromatographed title product, 0.30 g.; ¹ H-nmr (CDCl₃) delta(300 MHz): 1.30 (6H, complex), 1.39 (3H, s), 1.64 (3H, s), 4.0-4.7 (10H,complex), 4.92 (1H, d, J=10 Hz), 5.22 (2H, s), 5.55 (1H, d, J=4 Hz),7.42 (5H, s).

EXAMPLE C42 Benzyl6-beta-[S-1-(N-(Dimethylcarbamoylmethyl)-N-methylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example C1, using 1:19 methanol:ethyl acetate aseluant, title product of Preparation F1 (600 mg., 1.6 mmols) and2-(methylamino)-N,N-dimethylacetamide (0.72 g., 6.2 mmols) wereconverted to instant title product, 0.50 g.; tlc Rf 0.5 (1:9methanol:ethyl acetate); ¹ H-nmr (CDCl₃) delta (reflecting the two amideconformers in about 1:2 ratio): 1.36 (3H, s), 1.61 (3H, s), 2.93 (7H,br.s), 3.17 (2H, s), 3.8-4.3 (3H, complex), 4.35 (1H, br.s), 4.65 (0.3H,d, J=10 Hz), 4.84 (0.7H, d, J=10 Hz), 5.11 (2H, s), 5.40 (1H,overlapping doublets), 7.3 (5H, s).

EXAMPLE C43 Benzyl6-beta-[S-1-(N-(Methylcarbamoylmethyl)-N-methylcarbamoyl)-1-hydroxymethyl]penicillanate

By the procedure of Example C1, using 1:9 methanol:ethyl acetate aseluant, title product of Preparation F1 (600 mg., 1.6 mmols)2-(methylamino)-N-methylacetamide (0.63 g., 6.2 mmols) were converted toinstant title product, 0.50 g.; tlc Rf 0.55 (1:9 methanol:ethylacetate); ¹ H-nmr (CDCl₃) delta (reflecting the amide conformers inabout 2:3 ratio): 1.38 (3H, s), 1.62 (3H, br. s), 2.74 (3H, br.d), 2.93(1.2H, s), 3.20 (1.8H, s), 3.8-4.2 (3H, complex), 4.43 (1H, s), 4.85(1H, br.d), 5.13 (2H, s), 5.45 (1H, overlapping doublets), 6.47 (0.6H,br.d), 6.74 (0.4H, br.d), 7.3 (5H, s).

EXAMPLE C44 Benzyl6-beta-[S-1-(N-(Carbamoylmethyl)-N-methylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of the preceding Example, title product of Preparation F1(516 mg., 1.3 mmols) and 2-(methylamino)acetamide (0.47 g., 5.3 mmols)were converted to instant title product, 0.32 g.; tlc Rf 0.45 (1:10methanol:ethyl acetate); ¹ H-nmr (CDCl₃) delta (300 MHz) (reflecting thetwo amide conformers in 2:3 ratio): 1.35 (1.2H, s), 1.36 (1.8H, s), 1.59(1.2H, s), 1.62 (1.8H, s), 2.97 (1.2H, s), 3.23 (1.8H, s), 3.71 (0.6H,d, J=16 Hz), 3.90 (0.4H, d, J=18 Hz), 4.05 (1H, complex), 4.28 (0.6H, d,J=16 Hz), 4.41 (0.4H, J=18 Hz), 4.46 (0.4H, s), 4.49 (0.6H, s), 4.86(1H, complex), 5.18 (2H, s), 5.49 (0.6H, d, J=4 Hz), 5.54 (0.4H, d, J=4Hz), 6.51 (0.6H, br.s), 6.62 (0.6H, br.s), 6.20 (0.4H, br.s), 6.86(0.4H, br.s), 7.38 (5H, s).

EXAMPLE C45 Benzyl6-beta-[R-1-(N-Methyl-N-phenylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example C23, title product of Example F2 (0.8 g., 2.06mmols) and N-methylaniline (0.89 ml., 8.26 mmols) were converted toinstant title product, 0.43 g.; tlc Rf 0.35 (1:4 ethyl acetate:CHCl₃); ¹H-nmr (CDCl₃) delta (300 MHz) (reflecting the 2 amide conformers in 2:3ratio): 1.26 (3H, s), 1.34 (3H, s), 3.37 (3H, s), 3.80 (1H, dd, J=4 Hz,8 Hz), 4.37 (1H, s), 4.73 (1H, t), 5.20 (2H, s), 5.48 (1H, d, J=4 Hz),7.3-7.5 (10H, aromatics).

EXAMPLES C46-C78

Using the method of Examples C1-C45 above, the following additionalcompounds were prepared. Shown in sequence is the Example No., thecompound prepared, chromatography eluant, the amount prepared, itsphysical properties, and the starting materials and amounts thereof.

C46. Benzyl6-beta-[S-1-(S-2-(methoxycarbonyl)pyrrolidinocarbonyl)-1-hydroxymethyl]penicillanate;3:7 ethyl acetate:CHCl₃, 0.52 g.; ¹ H-nmr (CDCl₃) delta (ppm) 1.35 (3H,s), 1.63 (3H, s), 1.8-2.3 (4H, complex), 3.70 (3H, s), 3.7-4.0 (3H,complex), 4.06 (1H, dd, J=4 Hz, 10 Hz), 4.45 (1H, s), 4.82 (1H, d, J=10Hz), 5.18 (2H, s), 5.48 (1H, d, J=4 Hz), 7.40 (5H, s); product ofPreparation F1 (0.60 g.; 0.0016 mol) and L-proline methyl ester (0.80g., 0.0062 mol).

C47. Benzyl6-beta-[S-1-(N-(carbamoylmethyl)-N-benzylcarbamoyl)-1-hydroxymethyl]penicillanate;ethyl acetate; 0.31 g.; ¹ H-nmr (CDCl₃) delta (reflecting two rotamersin about 1:1 ratio) 1.33 (3H, br. s), 1.43 (1.5H, s), 1.56 (1.5H, s),3.4-4.3 (3H, complexes), 4.38 (1H, s), 4.6-5.1 (complexes), 5.13 (2H,s), 5.43 (0.5H, d, J=4 Hz), 5.52 (0.5H, d, J=4 Hz), 6.1-6.8 (2H,complex), 7.2-7.4 (10H, aromatics); product of Preparation F1 (0.60 g.,0.0016 mol) and 2-(benzylamino)-acetamide (1.0 g., 0.0062 mol).

C48. Benzyl6-beta-[S-1-(N,N-di(N-methylcarbamoylmethyl)carbamoyl)-1-hydroxymethyl]penicillanate;7:93 methanol:ethyl acetate; 0.15 g.; tlc Rf 0.25 (1:9 methanol:ethylacetate); ¹ H-nmr (CDCl₃) delta (300 MHz) 1.35 (3H, s), 1.58 (3H, s),2.80 (6H, m), 3.69 (1H, d, J=16 Hz), 3.9-4.2 (3H, complex), 4.46 (1H,s), 4.6-4.8 (2H, complex), 5.18 (2H, s), 5.45 (1H, d, J=4 Hz), 7.40 (5H,s), 7.52 (1H, m), 8.80 (1H, m); product of Preparation F1 (0.60 g.,0.0016 mol) and di(N-methylcarbamoylmethyl)amine (1.0 g., 0.0064 mol).

C49. Benzyl6-beta-[S-1-(N-ethyl-N-phenylcarbamoyl)-1-hydroxymethyl]penicillanate,1:4 ethyl acetate:CHCl₃ ; 0.39; tlc Rf 0.15 (1:4 ethyl acetate:CHCl₃),Rf 0.6 (1:1 ethyl acetate:CHCl₃); ¹ H-nmr (CDCl₃) delta (300 MHz) 1.16(3H, t), 1.37 (3H, s), 1.44 (3H, s), 3.6-4.0 (2H, m), 4.02 (1H, dd, J=4,10 Hz), 4.42 (1H, s), 4.48 (1H, d, J=10 Hz), 5.20 (2H, s), 5.33 (1H, d,J=4 Hz), 7.3-7.5 (9H, complex); product of Preparation F1 (0.80 g.,0.0021 mol) and N-ethylaniline (1.04 ml., 0.0083 mol).

C50. Benzyl6-beta-[S-1-(1,2,3,4-tetrahydroquinolinocarbonyl)-1-hydroxymethyl]penicillanate;CHCl₃ ; tlc Rf 0.55 (3:7 ethyl acetate:CHCl₃ ; ¹ H-nmr (CDCl₃) delta(300 MHz) 1.28 (6H, s), 1.36 (1H, m), 1.62 (1H, m), 1.87 (1H, m), 2.13(1H, m), 2.78 (2H, complex), 3.39 (1H, m), 3.69 (1H, m), 4.13 (1H, dd,J=4 Hz, 10 Hz), 4.25 (1H, m), 4.42 (1H, s), 5.00 (1H, br. d), 5.16 (2H,s), 5.33 (1H, m), 7.1-7.6 (9H, aromatics); product of Preparation F1(1.0 g., 0.0026 mol) and 1,2,3,4-tetrahydroquinoline (1.2 ml., 1.3 g.,0.010 mol).

C51. Benzyl6-beta-[S-1-(N-ethyl-N-(4-benzyloxyphenyl)carbamoyl)-1-hydroxymethyl]penicillanate;1:9 hexane:CHCl₃ ; 0.40 g., ¹ H-nmr (CDCl₃) delta (300 MHz) 1.12 (3H,t), 1.35 (3H, s), 1.42 (3H, s), 3.10 (1H, br. s), 3.64 (1H, m), 3.78(1H, m), 4.02 (1H, dd, J=4 Hz, 10 Hz), 4.40 (1H, s), 4.44 (1H, d, J=10Hz), 5.10 (2H, s), 5.17 (2H, s), 5.36 (1H, d, J=4 Hz), 7.0-7.5 (14H,aromatics); product of Preparation F1 (0.80 g., 0.0021 mol) andN-[4-(benzyloxy)phenyl]ethylamine (1.87 g., 0.0083 mol).

C52. Benzyl6-beta-[S-1-(N-ethyl-N-(3-benzyloxyphenyl)carbamoyl)-1-hydroxymethyl]penicillanate;CHCl₃, then 1:9 ethyl acetate:CHCl₃ (twice chromatographed); 0.11 g., ;¹ H-nmr (CDCl₃) delta (300 MHz); 1.15 (3H, t), 1.37 (3H, s), 1.46 (3H,s), 2.80 (1H, br.d), 3.6-3.9 (2H, m), 4.00 (1H, dd, J=4 Hz, 10 Hz), 4.42(1H, s), 4.52 (1H, m), 5.11 (2H, s), 5.20 (2H, s), 5.33 (1H, d, J=4 Hz),6.9-7.5 (14H, aromatics); product of Preparation F1 (0.80 g., 0.0021mol) and N-[3-(benzyloxy)phenyl]ethylamine (1.87 g., 0.0083 mol).

C53. Benzyl6-Beta-[S-1-(1-(methoxycarbonyl)isoindolinocarbonyl)-1-hydroxymethyl]penicillanate;1:9 ethyl acetate:CHCl₃ ; tlc Rf 0.4 (1:9 ethyl acetate:CHCl₃); ¹ H-nmr(CDCl₃) delta (300 MHz), reflecting C-1 isoindolino diastereoisomers andtwo amide rotamers of one of those isomers in near equal amounts, 1.36(1.7H, s), 1.39 (1.3H, s), 1.62 (2.1H, br.s), 1.67 (0.9H, s), 3.74 (1H,s), 3.76 (2H, s), 4.0-4.2 (1H, complex), 4.47 (0.26H, s), 4.50 (0.46H,s), 4.51 (0.28H, s), 4.8-5.4 (3H, overlapping multiplets), 5.20 (2H, s),5.56 (0.8H, complex), 5.60 (0.2H, d, J=4 Hz), 5.65 (0.26H, br, s), 5.73(0.46H, br.s), 6.26 (0.23H, br.s), 7.3-7.5 (9H, aromatic complex);product of Preparation F1 (0.40 g., 0.001 mol) and methylisoindoline-1-carboxylate (0.49 g., 0.0028 mol).

C54. Benzyl6-beta-[S-1-(N-(N-isopropylcarbamoylmethyl)-N-benzyl)carbamoyl-1-hydroxymethyl]penicillanate;3:7 ethyl acetate:CHCl₃ ; 0.34 g.; tlc Rf 0.3 (1:1 ethyl acetate:CHCl₃);¹ H-nmr (CDCl₃) delta (300 MHz), revealing amide conformers in about 1:1ratio, 0.9-1.1 (6H, complex), 1.30 (1.5H, s), 1.31 (1.5H, s), 1.43(1.5H, s), 1.52 (1.5H, s), 3.6-4.2 (5.5H, complex), 4.40 (1H, s),4.5-5.1 (2.5H, complex), 5.14 (2H, s), 5.49 (0.5H, d, J=4 Hz), 5.53(0.5H, d, J=4 Hz), 5.95 (0.5H, br.d, J=8 Hz), 6.03 (0.5H, br.d, J=8 Hz),7.1-7.4 (10H, complex); product of Preparation F1 (0.60 g., 0.0016 mol)and 2-(benzylamino)-N-isopropylacetamide (1.2 g., 0.0064 mol).

C55. Benzyl6-beta-[S-1-(S-2-(carbamoyl)pyrrolidinocarbonyl)-1-hydroxymethyl]penicillanate;ethyl acetate; 0.26 g.; tlc Rf 0.7 (ethyl acetate); ¹ H-nmr (CDCl₃)delta (300 MHz), 1.37 (3H, s), 1.61 (3H, s), 1.97 (2H, m), 2.2-2.5 (2H,complex), 3.56 (2H, complex), 4.06 (1H, dd, J=4Hz, 10 Hz), 4.31 (1H, t),4.54 (1H, s), 5.18 (2H, s) 5.12 (1H, d, J=10 Hz), 5.72 (1H, d, J=4 Hz),7.37 (5H, s); product of Example F1 (0.60 g., 0.0016 mol) andL-prolinamide (0.73 g., 0.0064 mol).

C56. Benzyl6-beta-[S-1-(S-2-(N-methylcarbamoyl)pyrrolidinocarbonyl)-1-hydroxymethyl]penicillanate;ethyl acetate; 0.26 g.; tlc Rf 0.2 (ethyl acetate); ¹ H-nmr (CDCl₃)delta (300 MHz), reflecting amide rotamers in 1:3 ratio, 1.35 (0.75H,s), 1.37 (2.25H, s), 1.58 (0.75H, s), 1.61 (2.25H, s), 1.8-2.1 (4H,complex), 2.75 (3H, d), 3.5-4.0 (2H, complex), 4.05 (1H, dd, J=4 Hz, 10Hz), 4.44 (0.25H, s), 4.48 (0.75H, s), 4.5-4.8 (3H, complex), 5.19 (2H,s), 5.50 (1H, d, J=4 Hz), 6.69 (0.25H, d), 6.91 (0.75H, d), 7.38 (5H,s); product of Preparation F1 (0.60 g., 0.0016 mol) andN-methyl-L-prolinamide (0.82 g., 0.0064 mol).

C57. Benzyl6-beta-[S-1-(N,N-di(pyrrolidinocarbonylmethyl)carbamoyl-1-hydroxymethyl]penicillanate;1:19 CH₃ OH:ethyl acetate; 0.40 g.; ¹ H-nmr (CDCl₃) delta (300 MHz),1.35 (3H, s), 1.60 (3H, s), 1.7-2.1 (8H, complex), 3.3-3.5 (8H,complex), 4.07 (1H, dd, J=4 Hz, 10 Hz), 4.10 (2H, ABq), 4.46 (1H, s),4.51 (2H, ABq), 4.79 (1H, d, J=10 Hz), 5.18 (1H, s), 5.51 (1H, d, J=4Hz), 7.37 (5H, s); product of Preparation F1 (0.60 g., 0.0016 mol) anddi(pyrrolidinocarbonylmethyl)amine.

C58. Benzyl6-beta-[S-1-[N-(4-(2-hydroxyethyl)piperazinocarbonylmethyl)-N-benzylcarbamoyl]-1-hydroxymethyl]penicillanate;3:17 CH₃ OH:ethyl acetate; 19 mg.; ¹ H-nmr (CDCl₃) delta (300 MHz),reflecting two amide conformers in 1:2 ratio, 1.41 (2H, s), 1.43 (1H,s), 1.66 (2H, s), 1.68 (1H, s), 2.4-2.7 (4H, overlapping multiplets),3.0-3.2 (2H, m), 3.5-3.8 (4H, overlapping multiplets), 3.86 (2H, d),3.90 (0.33H, dd, J=4 Hz, 10 Hz), 4.06 (0.67H, dd, J=4 Hz, 10 Hz), 4.30(1.3H, t), 4.50 (0.67H, s), 4.55 (0.33H, s), 4.80 (0.33H, d, J=10 Hz),4.88 (0.67H, d, J=10 Hz), 5.22 (2H, s), 5.52 (0.33H, d, J=4 Hz), 5.55(0.67H, d, J=4 Hz), 7.3-7.5 (10H, aromatics); product of Preparation F1(0.60 g., 0.0016 mol) andN-[4-(2-hydroxyethyl)piperazinocarbonylmethyl]benzylamine (1.7 g.,0.0062 mol).

C59. Benzyl6-beta-[S-1-(4-(N-isopropylcarbamoylmethyl)piperazino)carbonyl-1-hydroxymethyl]penicillanate;1:49 CH₃ OH:ethyl acetate; 0.282 g.; tlc Rf 0.45 (1:9 CH₃ OH: ethylacetate) ¹ H-nmr (CDCl₃) delta, 1.16 (6H, d, J=8 Hz), 1.36 (3H, s), 1.60(3H, s), 2.4-2.6 (4H, complex), 3.01 (2H, s), 3.6-3.8 (5H, complex),4.03 (1H, dd, J=4 Hz, 10 Hz), 4.45 (1H, s), 4.85 (1H, d, J=10 Hz), 5.20(2H, s), 5.32 (1H, d, J=4 Hz), 6.89 (1H, d, J=8 Hz), 7.38 (5H, s);product of Preparation F1 (0.60 g.) and1-(N-isopropylcarbamoylmethyl)piperazine (1.14 g., 0.0062 mol).

C60. Benzyl6-beta-[S-1-(2,6-dimethylmorpholinocarbonyl)-1-hydroxymethyl]penicillanate;3:7 ethyl acetate:CHCl₃ ; 0.26 g.; tlc Rf 0.25 (3:7 ethylacetate:CHCl₃); ¹ H-nmr (CDCl₃) delta (300 MHz), reflecting two isomersin 1:1 ratio, possibly the amide rotamers of a singlemeso-2,6-dimethylmorpholine isomer, 1.16 (6H, d), 1.34 (3H, s), 1.61(3H, s), 2.36 (1H, t), 2.7-3.0 (1H, complex), 3.4-3.7 (2H, complex),3.9-4.1 (2H, complex), 4.30 (1H, t), 4.44 (1H, s), 4.78 (0.5H, d, J=10Hz), 4.86 (0.5H, d, J=11 Hz), 5.18 (2H, s), 5.50 (1H, d, J=4 Hz), 7.37(5H, s); product of Preparation F1 (0.60 g., 0.0016 mol) and2,6-dimethylmorpholine (commercial "mixture of isomers"; 0.79 ml., 0.74g., 0.0064 mol).

C61. Benzyl6-beta-[S-1-(N-(N-ethylcarbamoylmethyl)-N-benzylcarbamoyl)-1-hydroxymethyl]penicillanate;3:7 ethyl acetate:CHCl₃ ; 0.2 g.; tlc Rf 0.4 (1:1 ethyl acetate:CHCl₃);¹ H-nmr (CDCl₃) delta (300 MHz), reflecting two amide rotamers in 1:1ratio, 1.00 (1.5H, t), 1.06 (1.5H, t), 1.36 (3H, s), 1.48 (1.5H, s),1.57 (1.5H, s), 3.0-3.3 (2H, complex), 3.78 (1.5H, d, J=16 Hz), 3.9-4.3(4H, complex), 4.46 (1H, s), 4.62 (0.5H, d, J=16 Hz), 4.8-5.15 (3H,complex), 5.20 (2H, s), 5.55 (0.5H, d, J=4 Hz), 5.60 (0.5H, d, J=4 Hz),6.30 (0.5H, t), 6.44 (0.5H, t), 7.2-7.4 (10H, complex); the product ofPreparation F1 (0.60 g., 0.0016 mol) and2-(benzylamino)-N-ethylacetamide (1.2 g., 0.0064 mol).

C62. Benzyl6-beta-[S-1-(N-(1-methyl-4-piperidyl)-N-methylcarbamoyl)-1-hydroxymethyl]penicillanate;1:3 CH₃ OH:ethyl acetate; 0.162 g.; tlc Rf 0.1 (1:1 CH₃ OH:ethylacetate); ¹ H-nmr (CDCl₃) delta (300 MHz), reflecting two amide rotamersin about 3:5 ratio, 0.8-1.0 (2H, complex), 1.1-1.2 (2H, complex), 1.36(3H, s), 1.62 (3H, br.s), 1.5-2.1 (4H, complex), 2.26 (1.9H, s), 2.28(1.1H, s), 2.82 (1.1H, s), 2.92 (2H, complex), 3.01 (1.9H, s), 4.03 (1H,complex), 4.47 (1H, s), 4.80 (0.6H, d, J=10 Hz), 4.85 (0.4H, d, J=10Hz), 5.18 (2H, s), 5.48 (0.6H, d, J=4 Hz), 5.50 (0.4H, d, J=4 Hz), 7.37(5H, s); product of Preparation F1 (0.60 g., 0.0016 mol) and1-methyl-4-(methylamino)piperidine (0.82 g., 0.0064 mol).

C63. Benzyl6-beta-[S-1-(N-(2-morpholinoethyl)-N-benzylcarbamoyl)-1-hydroxymethyl]penicillanate;ethyl acetate; 0.166 g.; tlc Rf 0.3 (ethyl acetate; ¹ H-nmr (CDCl₃)delta (300 MHz), reflecting two amide conformers in 1:4 ratio, 1.35(0.6H, s), 1.38 (2.4H, s), 1.46 (0.6H, s), 1.60 (2.4H, s), 2.3-2.7 (6H,complex), 3.1-4.4 (1H, complex), 4.5-4.8 (5H, complex), 4.08 (0.8H, d),4.14 (1H, dd, J=4 Hz, J=10 Hz), 4.41 (0.2H, s), 4.49 (0.8H, s), 4.89(0.8H, d), 5.18 (2H, s), 5.52 (0.2H, d, J=4 Hz), 5.58 (0.8H, d, J=4 Hz),7.2-7.5 (10H, complex); product of Preparation F1 (0.43 g., 0.0011 mol)and N-(2-morpholinoethyl)benzylamine (0.85 g., 0.0038 mol).

C64. Benzyl6-beta-[S-1-(4-(2-hydroxyethyl)piperazinocarbonyl)-1-hydroxymethyl]penicillanate;3:7 ethyl acetate:CHCl₃, 1:19 CH₃ OH:ethyl acetate (twicechromatographed); 0.14 g.; tlc Rf 0.6 (1:1 CH₃ OH:ethyl acetate); ¹H-nmr (CDCl₃) delta (300 MHz) 1.37 (3H, s), 1.62 (3H, s), 2.4-2.7 (6H,complex), 3.24 (2H, br.s), 3.5-3.9 (6H, complex), 4.03 (1H, dd, J=4 Hz,10 Hz), 4.46 (1H, s), 4.86 (1H, d, J=10 Hz), 5.20 (2H, s), 5.51 (1H, d,J=4 Hz), 7.4 (5H, s); product of Preparation F1 (0.70 g., 0.0018 mol)and 1-(2-hydroxyethyl)piperazine (0.94 g., 0.0072 mol).

C65. Benzyl6-beta-[S-1-(4-benzylpiperazinocarbonyl)-1-hydroxymethyl]penicillanate;ethyl acetate; 0.346 g.; tlc Rf 0.65 (ethyl acetate); ¹ H-nmr (CDCl₃)delta (300 MHz) 1.41 (3H, s), 1.66 (3H, s), 2.4-2.6 (4H, complex),3.5-3.8 (4H, complex), 4.07 (1H, dd, J=4 Hz, 10 Hz), 4.51 (1H, s), 4.90(1H, d, J=10 Hz), 5.24 (2H, s), 5.56 (1H, d, J=4 Hz), 7.3-7.5 (10H,aromatics); product of Preparation F1 (0.60 g., 0.0016 mol) andN-benzylpiperazine (1.1 ml., 1.1 g., 0.0064 mol).

C66. Benzyl6-beta-[S-1-(N-(N-ethylcarbamoylmethyl)-N-ethylcarbamoyl)-1-hydroxymethyl]penicillanate;7:3 ethyl acetate:CHCl₃ ; 0.13 g.; tlc Rf 0.35 (ethyl acetate); ¹ H-nmr(CDCl₃) delta (300 MHz), reflecting two amide rotamers in about 3:5ratio, 1.12 (3H, overlapping triplets), 1.27 (3H, overlapping triplets),1.38 (1.12H, s), 1.39 (1.88H, s), 1.61 (1.12 H, s), 1.64 (1.88H, s),3.1-4.3 (7H, overlapping multiplets), 4.48 (0.38H, s), 4.50 (0.62H, s),4.85 (0.38H, d, J=10 Hz), 4.92 (0.62H, d, J=10 Hz), 5.22 (2H, s), 5.55(0.62H, d, J=4 Hz), 5.57 (0.38H, d, J=4Hz), 6.36 (1H, m), 7.4 (5H, s);product of Preparation F1 (0.60 g., 0.0016 mol) and2-(ethylamino)-N-ethylacetamide (0.83 g., 0.0064 mol).

C67. Benzyl6-beta[S-1-(N-(N-propylcarbamoylmethyl)-N-benzylcarbamoyl)-1-hydroxymethyl]penicillanate;1:9 ethyl acetate:CHCl₃ ; 0.32 g.; tlc Rf 0.25 (3:7 ethylacetate:CHCl₃); ¹ H-nmr (CDCl₃) delta (300 MHz), reflecting two amiderotamers in 1:1 ratio, 0.83 (1.5H, t), 0.86 (1.5H, t), 1.35 (1.5H, s),1.36 (1.5H, s), 1.40 (2H, m), 1.47 (1.5H, s), 1.56 (1.5H, s), 3.0-3.2(2H, complex), 3.76 (0.5H, d), 3.90 (0.5H, d), 4.0-4.2 (2H, overlappingmultiplets), 4.44 (0.5H, s), 4.46 (0.5H, s), 4.61 (0.5H, d), 4.8-5.0(1.5H, complex), 5.04 (0.5H, d), 5.19 (2H, s), 5.53 (0.5H, d, J=4 Hz),5.58 (0.5H, d), 6.26 (0.5H, br.t), 6.40 (0.5H, br.t), 7.2-7.5 (10H,aromatics); product of Preparation F1 (0.60 g., 0.0016 mol) and2-(benzylamino)-N-propylacetamide (1.3 g., 0.0064 mol).

C68. Benzyl6-beta-[S-1-[S-(2-(N-ethylcarbamoyl)pyrrolidino)carbonyl]-1-hydroxymethyl]penicillanate;ethyl acetate; 0.225 g.; tlc Rf 0.2 (ethyl acetate); ¹ H-nmr (CDCl₃)delta (300 MHz), reflecting two amide rotamers in about 1:5 ratio, 1.08(3H, t), 1.35 (3H, s), 1.57 (0.5H, s), 1.60 (2.5H, s), 1.7-2.2 (4H,complex), 3.1-3.3 (2H, complex), 3.5-3.8 (3H, complex), 4.01 (1H, dd,J=4 Hz, 10 Hz), 4.42 (0.17H, s), 4.46 (0.83H, s), 4.76 (1H, complex),5.18 (2H, s), 5.48 (0.83H, d, J=4 Hz), 5.51 (0.17H, d, J=4 Hz), 6.8 (1H,br.s), 7.26 (5H, s), 7.36 (5H, s); product of Preparation F1 (0.60 g.,0.0016 mol) and N(amide)ethyl-L-prolinamide (0.91 g., 0.0064 mol).

C69. Benzyl6-beta-[S-1-[N-(N-(2-methylpropyl)carbamoylmethyl)-N-(2-methylpropyl)carbamoyl]-1-hydroxymethyl]penicillanate;3:7 ethyl acetate:CHCl₃ ; 0.12 g.; ¹ H-nmr (CDCl₃) delta (300 MHz)reflecting two amide rotamers in about 1:1 ratio, 0.8-1.0 (12H,complex), 1.38 (3H, br.s), 1.61 (3H, br.s), 1.76 (1H, m), 2.04 (1H, m),2.9-3.2 (3H, complex), 3.47 (0.5H, m), 3.66 (0.5H, m), 3.9-4.2 (2H,complex), 4.3-4.6 (2H, complex), 4.91 (1H, m), 5.22 (2H, br.s), 5.55(1H, m), 6.63 (1H, m), 7.4 (5H, br.s); product of Preparation F1 (0.60g., 0.0016 mol) and2-[(2-methylpropyl)amino]-N-(2-methylpropyl)acetamide (1.1 g., 0.0064mol). (2-methylpropyl)acetamide (1.1 g., 0.0064 mol).

C70. Benzyl6-beta-[S-(N-(2-morpholinoethyl)-N-ethylcarbamoyl)-1-hydroxymethyl]penicillanate;1:99 CH₃ OH:ethyl acetate; tlc Rf 0.35 (1:19 CH₃ OH:ethyl acetate); 0.11g.; ¹ H-nmr (CDCl₃) delta (300 MHz), reflecting two amide rotamers inabout 1:2 ratio, 0.85 (1H, t), 1.10 (2H, t), 1.33 (3H, s), 1.58 (3H, s),2.3-3.0 (6H, complex), 3.2-4.0 (8H, complex), 4.0-4.1 (1H, complex),4.45 (1H, s), 4.78 (1H, d, J=10 Hz), 5.16 (2H, s), 5.47 (0.3H, d, J=4Hz), 5.51 (0.7H, d, J=4 Hz), 7.35 (5H, s); product of Preparation F1(0.60 g., 0.0016 mol) and N-[2-(ethylamino)ethyl]morpholine (1.0 g.,0.0064 mol).

C71. Benzyl6-beta-[S-1-[N-(R-alpha-methylbenzyl)carbamoyl]-1-hydroxymethyl]penicillanate;1:4 ethyl acetate:CHCl₃ ; 0.35 g.; tlc Rf 0.4 (1:4 ethyl acetate:CHCl₃);¹ H-nmr (CDCl₃) delta (300 MHz) 1.35 (3H, s), 1.47 (3H, d, J=7 Hz), 1.62(3H, s), 3.62 (1H, d, J=3 Hz), 3.77 (1H, dd, J=4 Hz, 10 Hz), 4.44 (1H,s), 4.70 (1H, dd, J=3 Hz, 10 Hz), 5.06 (1H, m), 5.16 (2H, Abq), 5.47(1H, d, J=4 Hz), 6.98 (1H, d), 7.3-7.4 (10H, aromatics); product ofPreparation F1 (0.80 g., 0.0021 mol) and R-(+)-alpha-methylbenzylamine(0.266 ml., 0.0021 mol).

C72. Benzyl6-beta-[S-1-[N-(S-alpha-methylbenzyl)carbamoyl]-1-hydroxymethyl]penicillanate;1:4 ethyl acetate:CHCl₃ ; 0.18 g.; ¹ H-nmr (CDCl₃) delta (300 MHz), 1.36(3H, s), 1.48 (3H, d, J=8 Hz), 1.60 (3H, s), 3.86 (1H, dd, J=4 Hz, 8Hz), 4.42 (1H, s), 4.63 (1H, d, J=8 Hz), 5.06 (1H, m), 5.17 (2H, ABq),5.50 (1H, d, J=4 Hz), 6.94 (1H, d, J=9 Hz), 7.2-7.4 (10H, aromatics);product of Preparation F1 (0.80 g., 0.0021 mol) andS-(-)-alpha-methylbenzylamine (0.266 ml., 0.0021 mol).

C73. Benzyl6-beta-[S-1-(N-benzhydrylcarbamoyl)-1-hydroxymethyl]penicillanate; 1:19ethyl acetate:CHCl₃); 0.45 g.; ¹ H-nmr (CDCl₃) delta (300 MHz), 1.33(3H, s), 1.57 (3H, s), 3.77 (1H, dd, J=4 Hz, 8 Hz), 4.35 (1H, s), 4.66(1H, d, J=8 Hz), 5.07 (2H, ABq), 5.38 (1H, d, J=4 Hz), 6.06 (1H, d, J=9Hz), 7.0-7.2 (15H, complex), 7.25 (1H, d, J=9 Hz); product ofPreparation F1 (0.8 g., 0.0021 mol) and benzhydrylamine (0.71 ml.,0.0041 mol).

C74. Benzyl6-beta-[S-1-(N-[N-(2-morpholinoethyl)carbamoylmethyl]-N-benzylcarbamoyl)-1-hydroxymethyl]penicillanate;1:99 CH₃ OH:ethyl acetate (1 l.) then 1:9 CH₃ OH:ethyl acetate (1.5 l.);0.23 g.; tlc Rf 0.5 (1:9 CH₃ OH:ethyl acetate; ¹ H-nmr (CDCl₃) delta(300 MHz), reflecting amide rotamers in about 7:9 ratio, 1.30 (1.3H, s),1.32 (1.7H, s), 1.42 (1.3H, s), 1.54 (1.7H, s), 2.3-2.5 (6H, complex),3.0-3.8 (6H, complex), 3.95 (0.44H, dd, J=4 Hz, 10 Hz), 4.10 (0.56 H,dd, J=4 Hz, 10 Hz), 4.2-4.3 (1H, complex), 4.39 (0.44H, s), 4.41 (0.56H,s), 4.51 (0.44H, d, J=16 Hz), 4.72 (0.56H, d, J=10 Hz, 4.83 (0.44H, d,J=10 Hz), 4.92 (0.56H, d, J=14 Hz), 5.13 (2H, br.s), 5.46 (1H, complex),6.62 (0.56H, m), 6.91 (0.44H, m), 7.1-7.4 (10H, complex); product ofPreparation F1 (0.60 g., 0.0016 mol) and2-benzylamino-N-(2-morpholinoethyl)acetamide (1.8 g., 0.0064 mol).

C75. Benzyl6-beta-[S-1-(S-2-(N,N-dimethylcarbamoyl)pyrrolidinocarbonyl)-1-hydroxymethyl]penicillanate;1:24 CH₃ OH:ethyl acetate; 0.33 g.; tlc Rf 0.5 (1:9 CH₃ OH:ethylacetate); ¹ H-nmr (CDCl₃) delta (300 MHz), reflecting amide rotamers inabout 1:2 ratio, 1.32 (3H, s), 1.56 (1H, s), 1.59 (2H, s), 1.7-2.2 (4H,complex), 2.88 (2H, s), 2.90 (1H, s), 3.00 (1H, s), 3.03 (2H, s),3.5-3.9 (3H, complex), 3.9-4.1 (1H, complex), 4.41 (1H, s), 4.7-4.9 (1H,complex), 5.10 (2H, ABq), 5.41 (0.67H, d, J=4 Hz), 5.44 (0.33H, d, J=4Hz), 7.3 (5H, s); product of Preparation F1 (0.60 g., 0.0016 mol) andthe N,N-dimethyl amide of L-proline (0.24 g., 0.0017 mol).

C76. Benzyl6-beta-[S-1-(1,4-diazabicyclo[3.3.2]non-4-ylcarbonyl)-1-hydroxymethyl]penicillanate;gradient elution with 1 l. each 1:12, 1:9, 1:7, 1:5, 1:1 CH₃ OH:ethylacetate and finally CH₃ OH; 0.11 g.; tlc Rf 0.1 (1:1 CH₃ OH:ethylacetate); ¹ H-nmr (CDCl₃) delta (300 MHz), reflecting amide rotamers inabout 1:3 ratio, 1.36 (3H, s), 1.59 (3H, s), 1.6-1.8 (2H, complex),1.9-2.1 (2H, complex), 2.8-3.1 (8H, complex), 3.70 (1H, t), 3.97 (0.75H,dd, J=4 Hz, 10 Hz), 4.05 (0.25H, dd, J=4 Hz, 10 Hz), 4.41 (1H, s), 4.48(1H, br.s), 4.78 (1H, d, J=10 Hz), 5.15 (2H, s), 5.42 (0.25H, d, J=4Hz), 5.47 (0.75H, d, J=4 Hz), 7.32 (5H, s); product of Preparation F1(0.60 g., 0.0016 mol) and 1,4-diazabicyclo[3.2.2]nonane (0.20 g., 0.016mol).

C77 Benzyl6-beta-[S-1-(S-2-(pyrrolidinocarbonyl)pyrrolidinocarbonyl)-1-hydroxymethyl]penicillanate;1:99 CH₃ OH:ethyl acetate; 0.32 g.; tlc Rf 0.45 (1:9 CH₃ OH:ethylacetate; ¹ H-nmr (CDCl₃) delta (300 MHz), reflecting amide rotamers inabout 3:7 ratio, 1.30 (3H s), 1.54 (0.9H, s), 1.57 (2.1H, s), 1.7-2.2(8H, complex), 3.2-3.9 (6H, complex), 4.0 (1H, complex), 4.40 (1H, s),4.42 (0.3H, m), 4.54 (0.7H, m), 4.68 (0.3H, d, J=10 Hz), 4.75 (0.7H, d,J=9 Hz), 5.10 (2H, complex), 5.39 (0.7H, d, J=4 Hz), 5.44 (0.3H, d, J=4Hz), 7.28 (5H, s); product of Preparation F1 (0.60 g, 0.0016 mol) andthe pyrrolidine amide of L-proline (0.26 g., 0.016 mol).

C78. Benzyl6-beta-[S-1-(N-methyl-N-(4-hydroxyphenyl)carbamoyl)-1-hydroxymethyl]penicillanate;CHCl₃ ; 0.21 g.; tlc Rf 0.4 (1:19 ethyl acetate:CHCl₃); ¹ H-nmr (CDCl₃)delta (300 MHz) 1.36 (3H, s), 1.62 (3H, s), 2.76 (3H, s), 3.93 (1H, dd,J=4 Hz, 10 Hz), 4.49 (1H, s), 4.90 (1H, d, J=10 Hz), 5.13 (2H, ABq),5.49 (1H, d, J=4 Hz), 6.51 (2H, d, J=9 Hz), 6.88 (2H, d, J=9 Hz), 7.31(5H, s); product of Preparation F1 (0.774 g., 0.0020 mol) andN-methyl-p-hydroxyaniline (0.308 g., 0.0022 mol).

METHOD D--OXIDATION REACTIONS EXAMPLE D1 Benzyl6-beta-[S-1-(Dimethylcarbamoyl)-1-hydroxymethyl]penicillanate 1-alpha-and 1-beta-Oxide

Title product of Example B1 (2.0 g., 0.0051 mol) was slurried in 20 ml.of ethyl acetate and cooled to 0°. m-Chloroperbenzoic acid (80%, 1.1 g.,0.0051 mol) was added and the reaction stirred for 20 minutes at 0°,complete solution occurring within 1 minute of the peracid addition. Thereaction mixture was washed 5×15 ml. cold saturated NaHSO₃, 5×15 ml.cold saturated NaHCO₃ and 1×15 ml. brine, dried and stripped to a solidfoam (2.2 g.). The foam was chromatographed on 90 g. silica gel,collecting 25 ml. fractions. Fractions 48-80 were stripped to yieldtitle 1-beta-oxide as an oil (1.0 g.) which was crystallized from CHCl₃and ether, 0.60 g.; mp 159°-160°; tlc Rf 0.3 (1:1 ethyl acetate:CHCl₃);¹ H-nmr (CDCl₃) delta (TMS): 1.06 (3H, s), 1.56 (3H, s), 2.93 (3H, s),3.13 (3H, s), 3.6 (1H, br.s), 4.05 (1H, dd, J=5 Hz, 9 Hz), 4.59 (1H, s),5.07 (1H, d, J=5 Hz), 5.20 (2H, Abq), 5.43 (1H, br.d, J=9 Hz), 7.35 (5H,s). Fractions 125-135 were stripped to yield title alpha-oxide, 0.20 g.;tlc Rf 0.15 (1:1 ethyl acetate:CHCl₃), ¹ H-nmr (CDCl₃) delta (TMS): 1.20(3H, s), 1.50 (3H, s), 2.96 (6H, br.s), 4.03 (1H, m, J values obscuredby residual ethyl acetate in sample), 4.34 (1H, s), 4.68 (1H, d, J=4Hz), 4.86 (1H, br.m), 5.09 (2H, s), 7.3 (5H, s).

EXAMPLE D2 Benzyl6-beta-[S-1-(Pyrrolidinocarbonyl)-1-hydroxymethyl]penicillanate 1-alpha-and 1-beta-Oxide

With the initial mixture of products isolated as a solid foam (2.5 g.),and employing ethyl acetate as eluant, the procedure of the precedingExample was employed to convert title product of Example B3 (1.9 g.)into the less polar 1-beta-oxide, 1 g.; tlc Rf 0.4 (ethyl acetate); ¹H-nmr (CDCl₃) delta (TMS): 1.05 (3H, s), 1.56 (3H, s), 1.7-2.0 (4H,overlapping multiplets), 3.3-3.7 (5H, overlapping multiplets), 4.02 (1H,dd, J=5 Hz, 9 Hz), 4.54 (1H, s), 5.03 (1H, d, J=5 Hz), 5.17 (2H, ABq),5.16 (1H, br.d, J=9 Hz), 7.3 (5H, s); and the more polar 1-alpha-oxide,100 mg.; ¹ H-nmr (CDCl₃) delta (TMS): 1.27 (3H, s), 1.60 (3H, s),1.7-2.2 (4H, complex overlapping multiplets), 3.3-3.7 (4H, complexoverlapping multiplets), 4.17 (1H, dd, J values obscured by ethylacetate remaining in sample), 4.46 (1H, s), 4.76 (1H, br.m), 4.78 (1H,d, J=5 Hz), 5.20 (2H, s), 7.35 (5H, s).

EXAMPLE D3 Benzyl6-beta-[S-1-(Dimethylcarbamoyl)-1-hydroxymethyl]penicillanate1,1-Dioxide

Title product of Example B1 (0.20 g., 0.51 mmol) in 3 ml. ethyl acetatewas combined with m-chloroperbenzoic acid (80%, 0.27 g., 0.0013 mol) at0°-5°, then stirred 22 hours at ambient temperature, recooled to 0°-5°,washed 5×3 ml. cooled, saturated NaHSO₃, 5×3 ml. cold, saturated NaHCO₃,1×brine, dried, stripped to an oil (0.10 g.) and chromatographed on 4 g.silica gel with 3:7 ethyl acetate:CHCl₃ as eluant to yield titleproduct, 60 mg.; ¹ H-nmr (CDCl₃) delta (TMS): 1.26 (3H, s), 1.50 (3H,s), 2.96 (3H, s), 3.17 (3H, s), 3.95 (1H, v.br), 4.25 (1H, dd, J=5 Hz,10 Hz), 4.48 (1H, s), 4.95 (1H, d, J=5 Hz), 5.26 (2H, ABq), 5.46 (1H, d,J=10), 7.4 (5H, s).

EXAMPLE D4 Benzyl6-beta-[S-1-(Pyrrolidinocarbonyl)-1-hydroxymethyl]penicillanate1,1-Dioxide

By the procedure of the preceding Example, title product of Example B3(0.85 g., 0.002 mol) was converted to instant, chromatographed titleproduct, 90 mg.; ¹ H-nmr (CDCl₃) delta (TMS): 1.26 (3H, s), 1.49 (3H,s), 1.7-2.1 (4H, overlapping multiplets), 3.3-3.9 (5H, overlappingmultiplets), 4.20 (1H, dd, J=5 Hz, 9 Hz), 4.41 (1H, s), 4.89 (1H, d, J=5Hz), 4.95-5.40 (4H, overlapping multiplets), 7.3 (5H, s).

EXAMPLE D5 Benzyl6-beta-[S-1-(4-Hydroxypiperidinocarbonyl)-1-hydroxymethyl]penicillanate1,1-Dioxide

Title product of Example C7 (0.10 g., 0.22 mmol) and m-chloroperbenzoicacid (85%, 0.135 g., 0.67 mmol) in 20 ml. ethyl acetate were stirredunder N₂ for 20 hours, washed 4×10 ml. saturated NaHSO₃, 3×10 ml.saturated NaHCO₃, 2×10 ml. H₂ O and 1×10 ml. brine, dried and strippedon an 80 mg. residue. The latter was chromatographed on 30 g. silica gelwith ethyl acetate as eluant, collecting 20 ml. fractions. Fractions7-12 were combined and stripped to yield title product as a solid foam,55 mg.; tlc Rf 0.3 (ethyl acetate); ¹ H-nmr (CDCl₃) delta: 1.25 (3H, s),1.48 (3H, s), 1.2-2.1 (4H, complex), 2.33 (1H, complex), 3.0-3.6 (2H,complex), 3.6-4.2 (4H, complex), 4.21 (1H, dd, J =5 Hz, 9 Hz), 4.44 (1H,s), 4.91 (1H, d, J=5 Hz), 5.20 (2H, ABq), 5.40 (1H, broad complex), 7.3(5H, s).

EXAMPLE D6 Benzyl6-beta-[S-1-(N-Benzyl-N-methylcarbamoyl)-1-hydroxymethyl]penicillanate1,1-Dioxide

Using 3:7 ethyl acetate:CHCl₃ as eluant, the method of the precedingExample was used to convert title product of Example C16 (0.10 g., 0.21mmol) to instant title product, 33 mg.; ¹ H-nmr (CDCl₃) delta: 1.27 (3H,s), 1.50 (3H, s), 2.79 (1H, s), 3.01 (2H, s), 4.20 (1H, dd, J=5 Hz, 10Hz), 4.42 (1H, s), 4.62 (1H, d, J=5 Hz), 4.88 (1H, d, J=5 Hz), 5.11 (2H,ABq), 5.5 (1H, broad complex), 7.22 (5H, s), 7.33 (5H, s).

EXAMPLE D7 Benzyl6-beta-[S-1-(N-(2-Phenylethyl)-N-methylcarbamoyl)-1-hydroxymethyl]penicillanate1,1-Dioxide

Using 1:4 ethyl acetate:CHCl₃ as eluant, the method of Example D5 wasused to convert benzyl6-beta-[S-1-(N-(2-phenylethyl)-N-methylcarbamoyl)-1-hydroxymethyl]penicillanate(0.10 g, 0.21 mmol) to instant title product, about 30 mg.; ¹ H-nmr(CDCl₃) delta (300 MHz): 1.29 (3H, br.s), 1.54 (3H, s), 2.8-3.1 (2H,overlapping multiplets), 2.94 (1.2H, s), 3.08 (1.8H, s), 3.47 (0.6H,multiplet), 3.6-3.8 (1.4H, overlapping multiplets), 4.27 (1H,overlapping multiplets), 4.51 (1H, br.s), 4.98 (1H, overlappingdoublets), 5.21 (1.2H, ABq), 5.36 (0.8H, ABq), 5.46 (0.6H, d, J=10 Hz),5.54 (0.4H, d, J=9 Hz), 7.2-7.5 (10 Hz, aromatics), reflecting amiderotamers in 2:3 ratio.

EXAMPLE D8 Benzyl6-beta-[S-1-(1,2,3,4-Tetahydroisoquinolinocarbonyl)-1-hydroxymethyl]penicillanate1,1-Dioxide

Using CHCl₃ as eluant, the method of Example D5 was used to converttitle product of Example C11 (0.2 g., 0.92 mmol) to instant titleproduct, 0.12 g.; ¹ H-nmr (CDCl₃) delta: 1.26 (3H, s), 1.46 (3H, s),2.8-3.2 (2H, br.t), 3.3-4.4 (4H, complex overlapping multiplets), 4.44(1H, s), 4.8-5.0 (2H, complex), 5.20 (2H, ABq), 5.60 (1H, br.d), 7.2-7.5(9H, aromatics).

EXAMPLE D9 Benzyl6-beta-[S-1-(N-Methyl-N-phenylcarbamoyl)-1-hydroxymethyl]penicillanate1,1-Dioxide

Using 3:7 ethyl acetate:CHCl₃ as eluant, the method of Example D5 wasused to convert title product of Example C17 (0.14 g., 0.31 mmol) toinstant title product, 0.12 g.; ¹ H-nmr (CDCl₃) delta: 1.23 (3H, s),1.46 (3H, s), 3.24 (3H, s), 4.06 (1H, dd, J=5 Hz, 9 Hz), 4.30 (1H, s),4.80 (1H, d, J=5 Hz), 5.12 (2H, ABq), 7.3 (10H, aromatic).

EXAMPLE D10 Benzyl6-beta-[S-1-(4-Phenylpiperazinocarbonyl)-1-hydroxymethyl]penicillanate1,1-Dioxide

By the method of Example D7, the title product of Example C19 (0.30 g.,0.61 mmol) was converted to instant title product, 0.11 g.; ¹ H-nmr(CDCl₃) delta (300 MHz): 1.26 (3H, s), 1.50 (1.5H, s), 1.52 (1.5H, s),1.6-2.0 (4H, complex), 2.6-2.9 (3H, complex), 3.1-3.3 (2H, complex),4.2-4.4 (2H, complex), 4.51 (1H, s), 4.70 (1H, complex), 5.03 (1H, d,J=5 Hz), 5.24 (2H, ABq), 5.53 (0.5H, d), 5.57 (0.5H, d), 7.2-7.5 (10H,complex), reflecting a mixture of the two amide conformations in about1:1 ratio.

EXAMPLE D11 Benzyl6-beta-[S-1-(L-2-Benzyloxycarbonylpyrrolidinocarbonyl)-1-hydroxymethyl]penicillanate1,1-Dioxide

By the method of Example D9, title product of Example C22 (0.30 g., 0.54mmol) was converted to instant title product, 0.16 g.; ¹ H-nmr (CDCl₃)delta: 1.23 (3H, s), 1.46 (3H, s), 1.8-2.3 (4H, complex), 3.2-4.4 (5H,complex, 4.4-5.0 (2H, complex), 5.0-5.6 (5H, complex), 7.26 (5H, s),7.32 (5H, s).

EXAMPLE D12 Benzyl6-beta-[S-(N-Cyclohexyl-N-methylcarbamoyl)-1-hydroxymethyl]penicillanate1,1-Dioxide

By the method of Example D5, using 1:3 ethyl acetate:CHCl₃ as eluant,the title product of Example C23 (0.13 g., 0.28 mmol) was converted toinstant title product, 81 mg.; ¹ H-nmr (CDCl₃) delta (300 MHz): 1.28(3H, s), 1.53 (3H, s), 0.9-2.0 (10H, complex), 2.85 (1.3H, s), 3.04(1.7H, s), 3.8-4.1 (1H, complex), 4.2-4.4 (2H, complex), 4.48 (0.45H,s), 4.49 (0.55H, s), 4.94 (0.55H, d, J=5 Hz), 4.97 (0.45H, d, J=5 Hz),5.28 (2H, ABq), 5.44 (1H, complex), 7.4 (5H, s), reflecting the twoamide rotamers in a ratio of 4:5.

EXAMPLE D13 Benzyl6-beta-[S-1-(N-Benzyl-N-ethylcarbamoyl)-1-hydroxymethyl]penicillanate1,1-Dioxide

By the method of Example D5, using 1:9 ethyl acetate:CHCl₃ as eluant,title product of Example C25 (0.30 g., 0.62 mmol) was converted toinstant chromatographed title product, 0.14 g.; ¹ H-nmr (CDCl₃) delta(300 MHz) reflecting the 2 amide conformers in 3:4 ratio: 1.02 (1.3H,t), 1.16 (1.7H, t), 1.24 (3H, s), 1.49 (3H, s), 3.1-3.7 (3H,multiplets), 4.24 (1H, complex), 4.4-4.5 (1.6H, complex), 4.6-4.7 (1.2H,complex), 4.92 (0.57H, d, J=5 Hz), 4.94 (0.43H, d, J=5 Hz), 5.23 (2H,ABq), 5.52 (1H, complex), 7.2-7.4 (10H, aromatics).

EXAMPLE D14 Benzyl6-beta-[S-1-(N-Methyl-N-(4-methoxyphenyl)carbamoyl)-1-hydroxymethyl]penicillanate1,1-Dioxide

By the method of Example D5, without chromatography, title product ofExample C33 (0.1 g., 0.206 mmol) was converted to instant title product,0.105 g.; ¹ H-nmr (CDCl₃) delta: 1.18 (3H, s), 1.40 (3H, s), 3.16 (3H,s), 3.73 (3H, s), 4.06 (1H, dd, J=4 Hz, 10 Hz), 4.28 (1H, s), 4.77 (1H,d, J=10 Hz), 5.12 (1H, d, J=4 Hz), 6.97 (4H, ABq), 7.25 (5H, s).

EXAMPLE D15 Benzyl6-beta-[S-1-[N-(R-alpha-methylbenzyl)carbamoyl]-1-hydroxymethyl]penicillanate1,1-Dioxide

The product of Example C71 (0.12 g.) was converted to the presentproduct according to the method of the preceding Examples using 1:4ethyl acetate:CHCl₃ as eluant on chromatography, 0.11 g.; ¹ H-nmr(CDCl₃) delta (300 MHz), 1.21 (3H, s), 1.45 (3H, d, J=8 Hz), 1.50 (3H,s), 3.79 (1H, dd, J=5 Hz, 10 Hz), 4.48 (1H, s), 4.75 (1H, d, J=5 Hz),5.1-5.3 (3H, complex), 7.11 (1H, d, J=9 Hz), 7.2-7.4 (10 H, complex).

METHOD E--HYDROGENOLYSIS REACTIONS EXAMPLE E1 Sodium6-beta-(S-1-Carbamoyl-1-hydroxymethyl)penicillanate P 10% Pd/C (0.12 g.)was prehydrogenated in 2.5 ml. H₂ O at 4 atmospheres for 5 minutes.Title product of Example C1 (95 mg., 0.27 mmol) in 2.5 ml. THF andNaHCO₃ (21 mg., 0.25 mmols) were added and the mixture hydrogenated 20minutes at 4 atmospheres. Catalyst was recovered by filtration and thefiltrate stripped of THF, adjusted from pH 3.9 to 5.5 with dilute sodiumbicarbonate, and freeze dried to yield title product, 60 mg.; ¹ H-nmr(D₂ O) delta (300 MHz): 1.40 (3H, s), 1.58 (3H, s), 3.87 (1H, dd, J=4Hz, 10 Hz), 4.20 (1H, s), 4.65 (1H, d, J=10 Hz), 5.44 (1H, d, J=4 Hz).EXAMPLE E2 Sodium6-beta-[S-1-(Benzylcarbamoyl)-1-hydroxymethyl]penicillanate

10% Pd/C (60 mg.) was prehydrogenated in 5 ml. H₂ O. Title product ofExample C2 (60 mg., 0.13 mmol) in 5 ml. THF was added and the mixturehydrogenated at 4 atmospheres for 1 hour. The catalyst was recovered byfiltration, the filtrate was stripped of THF, and the aqueous residuewas extracted with ethyl acetate. The ethyl acetate was stripped toyield the free acid form of title product, 50 mg. The latter wasredissolved in ethyl acetate, layered with 10 ml. H₂ O and the pHadjusted to 6.0 with dilute NaHCO₃. The aqueous layer was freeze driedto yield title product, 7 mg.; ¹ H-nmr (D₂ O) delta (300 MHz): 1.34 (3H,s), 1.50 (3H, s), 3.79 (1H, dd, J=4 Hz, 10H), 4.12 (1H, s), 4.31 (2H,s), 4.61 (1H, d, J=10 Hz), 5.32 (1H, d, J=4 Hz), 7.23 (5H, m).

EXAMPLE E3 Sodium6-beta-[S-1-(tert-Butylcarbamoyl)-1-hydroxymethyl]penicillanate

By the procedure of Example E1, title product of Example C3 (0.20 g.,0.48 mmol) was converted to instant title product, 90 mg.; ¹ H-nmr (D₂O) delta (300 MHz): 1.25 (9H, s), 1.41 (3H, s), 1.56 (3H, s), 3.79 (1H,dd, J=4 Hz, 10 Hz), 4.16 (1H, s), 4.48 (1H, d, J=10 Hz), 5.36 (1H, d,J=4 HZ).

EXAMPLE E4 Sodium6-beta-[S-1-(phenylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example E2, title product of Example C4 (100 mg.) washydrogenated. Catalyst was recovered by filtration, THF was strippedfrom the filtrate, and the aqueous residue extracted 2×10 ml. ethylacetate, adjusted from pH 4.9 to 6.0 with dilute NaHCO₃ and freeze driedto yield title product, 37 mg.; ¹ H-nmr (D₂ O) delta (300 MHz): 1.39(3H, s), 1.54 (3H, s), 3.90 (1H, dd, J=4 Hz, 9 Hz), 4.16 (1H, s), 4.68(1H, d, J=9 Hz), 5.38 (1H, d, J=4 Hz), 7.36 (5H, m).

EXAMPLE E5 6-beta-[S-1-(Dimethylcarbamoyl)-1-hydroxymethyl]penicillanicAcid and Its Sodium Salt

By the method of Example E1, title product of Example B1 (3.9 g., 0.10mol) was converted to freeze dried title product as the sodium salt, 2.8g.; ¹ H-nmr (D₂ O) delta (300 MHz): 1.41 (3H, s), 1.56 (3H, s), 2.91(3H, s), 3.15 (3H, s), 3.91 (1H, dd, J=4 Hz, 10 Hz), 4.18 (1H, s), 4.89(1H, d, J=10 Hz), 5.34 (1H, d, J=4 Hz).

The sodium salt (0.5 g.) was dissolved in 3 ml. H₂ O and layered with 3ml. of ethyl acetate. The pH was adjusted from 5.6 to 2.0 with diluteHCl. The aqueous layer was extracted 2×3 ml. ethyl acetate. The threeorganic layers were combined, dried, stripped, and the residuecrystallized with ether to yield title product (free acid), 0.37 g.; ¹H-nmr (CDCl₃ /DMSO-d₆) delta (300 MHz): 1.51 (3H, s), 1.64 (3H, s), 2.94(3H, s), 3.14 (3H, s), 4.01 (1H, dd, J=4 Hz, 9 Hz), 4.36 (1H, s), 4.83(1H, d, J=9 Hz), 5.46 (1H, d, J=4 Hz.

EXAMPLE E6 Sodium6-beta-[S-1-(Diethylcarbamoyl)-1-hydroxymethyl]penicillanate

Washing 1×3 ml. ethyl acetate before freeze drying, the procedure ofExample E1 was employed to convert the title product of Example C5 (0.34g., 0.81 mmol) to instant title product, 97 mg; ¹ H-nmr (D₂ O) delta:1.10 (3H, t), 1.23 (3H, t), 1.47 (3H, s), 1.60 (3H, s), 3.40 (4H, 2overlapping q), 3.93 (1H, dd, J=4 Hz, 10 Hz), 4.18 (1H, s), 4.86 (1H, d,J=10 Hz), 5.37 (1H, d, J=4 Hz).

EXAMPLE E7 Sodium6-beta-[S-1-(Isopropylcarbamoyl)-1-hydroxymethyl]penicillanate

By the procedure of the preceding Example, S-title product of Example B2(25 mg., 0.06 mmol) was converted to instant title product, 15 mg.; ¹H-nmr(D₂ O) delta (300 MHz): 1.04 (6H, d, J=8 Hz), 1.37 (3H, s), 1.52(3H, s), 3.77 (1H, dd, J=4 Hz, 10 Hz), 3.83 (1H, m, J=8 Hz), 4.12 (1H,s), 4.50 (1H, d, J=10 Hz), 5.32 (1H, d, J=4 Hz).

EXAMPLE E8 Sodium6-beta-[S-1-(Pyrrolidinocarbonyl)-1-hydroxymethyl]penicillanate

By the method of Example E6, S-title product of Example B3 (2.09 g., 5mmol) was converted to instant title product, 1.3 g.; ¹ H-nmr (D₂ O)delta (300 MHz): 1.37 (3H, s), 1.54 (3H, s), 1.84 (4H, overlappingmultiplets), 3.33 (2H, t), 3.60 (2H, t), 3.91 (1H, dd, J=4 Hz, 10 Hz),4.15 (1H, s), 4.71 (1H, d, J=10 Hz), 5.31 (1H, d, J=4 Hz).

EXAMPLE E9 Sodium6-beta-[S-1-(Piperidinocarbonyl)-1-hydroxymethyl]penicillanate

By the method of Example E6, title product of Example B4 (1.6 g., 3.6mmol) was converted to instant title product. The resulting freeze driedproduct (0.70 g.) was slurried in a small amount of ethanol to producecrystalline title product, 0.25 g.; ¹ H-nmr (D₂ O) delta (300 MHz): 1.40(3H, s), 1.55 (3H, s), 1.58 (6H, complex overlapping multiplets),3.35-3.65 (4H, overlapping multiplets), 3.87 (1H, dd, J=4 Hz, 10 Hz),4.15 (1H, s), 4.90 (1H, d, J=10 Hz), 5.33 (1H, d, J=4 Hz).

EXAMPLE E10 Sodium6-beta-[S-1-(Perhydroazepinocarbonyl)-1-hydroxymethyl]penicillanate

By the method of Example E6, title product of Example C6 (0.33 g., 0.74mmol) was converted to instant title product, 0.19 g.; ¹ H-nmr (D₂ O)delta (300 MHz): 1.38 (3H, s), 1.52 (3H, s), 1.54 (8H, complexoverlapping multiplets), 3.0-3.8 (4H, complex overlapping multiplets),3.92 (1H, dd, J=4 Hz, 10 Hz), 4.15 (1H, s), 4.85 (1H, d, J=10 Hz), 5.34(1H, d, J=4 Hz).

EXAMPLE E11 Sodium6-beta-[S-1-(4-Hydroxypiperidinocarbonyl)-1-hydroxymethyl]penicillanate

By the method of Example E6, title product of Example C7 (0.13 g., 0.29mmol) was converted to present product, 70 mg.; ¹ H-nmr (D₂ O) delta(250 MHz): 1.48 (3/2H, s), 1.49 (3/2H, s), 1.62 (3/2H, s), 1.64 (3/2H,s), 1.6-2.2 (4H, overlapping multiplets), 3.0-3.5 (4H, overlappingmultiplets), 3.8-4.3 (4H, overlapping multiplets), 4.27 (1/2H, s), 4.28(1/2H, s), 4.99 (1/2H, d, J=9 Hz), 5.00 (1/2H, d, J=9 Hz), 5.43 (1H,overlapping doublets), reflecting a 1:1 mixture of the amide conformers.

EXAMPLE E12 Sodium6-beta-[S-1-1(Morpholinocarbonyl)-1-hydroxymethyl]penicillanate

By the method of Example E6, S-title product of Example B5 (0.5 g., 1.2mmol) was hydrogenated to instant freeze dried title product, 0.13 g.; ¹H-nmr (D₂ O) delta (90 MHz): 1.47 (3H, s), 1.60 (3H, s), 3.6-4.1 (9H,overlapping multiplets), 4.33 (1H, s), 5.03 (1H, d, J=10 Hz), 5.50 (1H,d, J=4 Hz).

EXAMPLE E13 Sodium6-beta-[S-1-(4-Formylpiperazinocarbonyl)-1-hydroxymethyl]penicillanate

By the procedure of Example E6, title product of Example C8 (0.26 g.,0.56 mmol) was converted to the above name product, 123 mg.; ¹ H-nmr (D₂O) delta (300 MHz): 1.52 (3H, s), 1.66 L (3H, s), 3.4-4.0 (8H, complexoverlapping multiplets), 4.05 (1H, dd, J=4 Hz, 10 Hz), 4.30 (1H, s),5.05 (1H, d, J=10 Hz), 5.50 (1H, d, J=4 Hz), 8.14 (1H, s).

EXAMPLE E14 Sodium6-beta-[S-1-(Methylcarbamoyl)-1-hydroxymethyl]penicillanate

Except that the initial pH was adjusted from 8.0 to 5.2 with 1N HCl, theprocedure of Example E1 was employed to convert title product of ExampleC9 (0.37 g., 0.98 mmols) to present freeze dried title product, 95 mg.;¹ H-nmr (D₂ O) delta (90 MHz): 1.46 (3H, s), 1.63 (3H, s), 2.76 (3H, s),3.88 (1H, dd, J=4 Hz, 9 Hz), 4.23 (1H, s), 4.65 (1H, d, J=9 Hz), 5.45(1H, d, J=4 Hz).

EXAMPLE E15 Sodium 6-beta-[S-B1-(2-Hydroxyethylcarbamoyl)-1-hydroxymethyl]penicillanate

By the procedure of Example E6, title product of Example C10 (0.325 g.,0.8 mmole) was converted to instant title product, 78 mg.; ¹ H-nmr (D₂O) delta (300 MHz): 1.40 (3H, s), 1.55 (3H, s), 3.29 (2H, t, J=6 Hz),3.59 (2H, t, J=6 Hz), 3.83 (1H, dd, J=4 Hz, 10 Hz), 4.16 (1H, s), 4.61(1H, d, J=10 Hz), 5.37 (1H, d, J=4 Hz).

EXAMPLE E16 Sodium6-beta-[S-1-(1,2,3,4-tetrahydroisoquinolinocarbonyl-1-hydroxymethy]penicillanate

By the method of Example E6 (no pH adjustment was necessary), titleproduct of Example C11 (0.25 g., 0.52 mmole) was converted to instanttitle product. A portion of the title product (53 mg.) precipitated fromthe aqueous residue on stripping THF, and was recovered by filtrationand combined with the remaining product (30 mg.) obtained by freezedrying the ethyl acetate washed aqueous filtrate; ¹ H-nmr (DMSO-d₆)delta (300 MHz): 1.34 (1.2H, s), 1.36 (1.8H, s), 1.44 (1.2H, s), 1.48(1.8H), 2.7-2.9 (2H, overlapping multiplets), 3.5-4.0 (5H, complexmultiplet), 4.60 (1H, s), 4.7 (1H, overlapping multiplets), 5.26 (1H, d,J=4 Hz), 7.19 (4H, s), reflecting a 2:3 mixture of amide conformers.

EXAMPLE E17 Sodium6-beta-[S-1-(N-Methyl-N-[2-hydroxyethyl]carbamoyl)-1-hydroxymethyl]penicillanate

Except that the initial pH was adjusted from 3.8 to 5.1 with 1N NaOH,the procedure of Example E1 was employed to convert title product ofExample C12 (0.20 g.) to present title product, 0.070 g.; ir (KBr) cm⁻¹1782, 1761; ¹ H-nmr (D₂ O) delta (300 MHz) 1.55 (3H, s), 1.69 L (1.5H,s), 1.71 (1.5H, s), 3.06 (1.5H, s), 3.33 (1.5H, s), 3.45-4.15 (5H,complex overlapping multiplets), 4.34 (1H, br.s), 5.06 (1H, overlappingdoublets), 5.51 (1H, overlapping doublets), reflecting an approximately1:1 mixture of amide rotamers.

EXAMPLE E18 Sodium6-beta-[S-1-(2-acetamidoethylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example E6, title product of Example C13 (204 mg., 0.45mmol) was converted to instant title product, 70 mg.; ¹ H-nmr (D₂ O)delta (300 MHz): 1.40 (3H, s) 1.56 (3H, s), 1.90 (3H, s), 3.26 (4H,complex overlapping multiplets), 3.79 (1H, dd, J=4 Hz, 10 Hz), 4.06 (1H,s), 4.58 (1H, d, J=10 Hz), 5.37 (1H, d, J=4 Hz).

EXAMPLE E19 Sodium6-beta-[R-1-(Isopropylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example E6, R-title product of Example B2 (80 mg., 0.20mmol) was converted to instant title product, 20 mg.; ¹ H-nmr (D₂ O)delta (300 MHz): 1.04 (6H, 2 doublets), 1.42 (3H, s), 1.57 (3H, s), 3.89(1H, multiplet), 3.94 (1H, dd, J=4 Hz, 9 Hz), 4.10 (1H, s), 4.47 (1H, d,J=9), 5.35 (1H, d, J=4 Hz).

EXAMPLE E20 Sodium6-beta-[R-1-(Morpholinocarbonyl)-1-hydroxymethyl]penicillanate

By the method of Example E6, R-title product of Example B5 (0.12 g.,0.28 mmol) was converted to instant title product, 80 mg.; ¹ H-nmr (D₂O) delta (300 MHz): 1.40 (3H, s), 1.53 (3H, s), 3.4-3.8 (overlappingmultiplets), 4.01 (1H, dd, J=4 Hz, 11 Hz), 4.08 (1H, s), 4.94 (1H, d,J=11 Hz), 5.39 (1H, d, J=4 Hz).

EXAMPLE E21 Sodium6-beta-[S-1-(Pyrrolidinocarbonyl)-1-hydroxymethyl]penicillanate1-beta-Oxide

By the method of Example E6, the 1-beta-oxide of Example D2 (1.0 g., 2.3mmol) was converted to instant title product, 0.60 g.; ¹ H-nmr (D₂ O)delta (300 MHz): 1.18 (3H, s), 1.54 (3H, s), 1.84 (4H, m), 3.3-3.7 (4H,overlapping multiplets), 4.03 (1H, dd, J=5 Hz, 9 Hz), 4.23 (1H, s), 5.06(1H, d, J=9 Hz), 5.19 (1H, s, J=5 Hz).

EXAMPLE E22 Sodium6-beta-[S-1-(Pyrrolidinocarbonyl)-1-hydroxymethyl]penicillanate1-alpha-Oxide

By the method of Example E6, the 1-alpha-oxide of Example D2 (100 mg.,0.23 mmol) was converted to instant title product, 65 mg.; ¹ H-nmr (D₂O) delta (300 MHz): 1.20 (3H, s), 1.54 (3H, s), 1.84 (4H, complexmultiplet), 3.34 (2H, t), 3.56 (2H, m), 4.15 (1H, dd, J=5 Hz, 8 Hz),4.16 (1H, s), 4.69 (1H, d, J=5 Hz), 4.91 (1H, d, J=8 Hz).

EXAMPLE E23 Sodium6-beta-[S-1-(Dimethylcarbamoyl)-1-hydroxymethyl]penicillanate1-beta-Oxide

10% Pd/C (600 mg.) was prehydrogenated in 10 ml. of H₂ O for 5 minutes.The 1-beta-oxide product of Example D1 (0.60 g.) in 10 ml. THF was addedand the mixture hydrogenated at 4 atmospheres for 20 minutes. Catalystwas recovered by filtration, the filtrate was stripped of THF, and theaqueous residue was adjusted from pH 2.2 to 4.5 with 0.1N NaOH, washed2×10 ml. ethyl acetate, and freeze dried to yield title product, 0.33g.; ¹ H-nmr (D₂ O) delta (90 MHz): 1.38 (3H, s), 1.74 (3H, s), 3.00 (3H,s), 3.17 (3H, s), 4.17 (1H, dd, J=5 Hz, 9 Hz), 4.37 (1H, s), 5.32 (1H,d, J=5 Hz), 5.35 (1H, d, J=9 Hz).

EXAMPLE E 24 Sodium6-beta-[S-1-(Pyrrolidinocarbonyl)-1-hydroxymethyl]penicillanate1,1-Dioxide

By the method of the preceding Example, title product of Example D4 (90mg., 0.2 mmol) was converted to instat title product, 35 mg.; ¹ H-nmr(D₂ O) delta (300 MHz): 1.34 (3H, s), 1.46 (3H, s), 1.87 (4H, complexmultiplet), 3.37 (2H, t), 3.59 (2H, m), 4.15 (1H, dd, J=5 Hz, 10 Hz),4.22 (1H, s), 5.07 (1H, d, J=5 Hz), 5.17 (1H, d, J=10 Hz).

EXAMPLE E25 Sodium6-beta-[S-1-1(Dimethylcarbamoyl)-1-hydroxymethyl]penicillanate1,1-Dioxide

By the method of Example 23, title product of Example D3 (60 mg.) wasconverted to instant title product, 50 mg.; ¹ H-nmr (D₂ O) delta: 1.41(3H, s), 1.52 (3H, s), 2.93 (3H, s), 3.14 (3H, s), 4.14 (1H, dd, J=5 Hz,10 Hz), 4.21 (1H, s), 5.04 (1H, d, J=5 Hz), 5.38 (1H, d, J=10 Hz).

EXAMPLE E26 Sodium6-beta-[S-1-Di(2-hydroxyethyl)carbamoyl-1-hydroxymethyl]penicillanate

By the method of Example E6, title product of Example C14 (90 mg.) wasconverted to instant title product, 23 mg.; ir (KBr) 1752 cm⁻¹ ; ¹ H-nmr(D₂ O) delta (300 MHz): 1.51 (3H, s), 1.65 (3H, s), 3.5-4.0 (8H,overlapping multiplet), 4.05 (1H, dd, J=4 Hz, 10 Hz), 4.30 (1H, s), 5.04(1H, d, J=10 Hz), 5.58 (1H, d, J=4 Hz).

EXAMPLE E27 Sodium6-beta-[S-1-(Dipropylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example E6, title product of Example C15 (110 mg.) wasconverted to instant title product, 40 mg.; ir (KBr) 1756 cm⁻¹ ; ¹ H-nmr(D₂ O) delta (300 Mz): 0.93 (6H, two overlapping triplets), 1.52 (3H,s), 1.5-1.8 (4H, overlapping multiplets), 1.66 (3H, s), 3.2-3.6 (4H,overlapping multiplets), 4.04 (1H, dd, J=4 Hz, 10 Hz), 4.30 (1H, s),4.94 (1H, d, J=10 Hz), 5.46 (1H, d, J=4 Hz).

EXAMPLE E28 Sodium6-beta-[S-1-(N-Benzyl-N-methylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example E6, title product of Example C16 (0.13 g.) wasconverted to instant title product, 50 mg.; ¹ H-nmr (D₂ O) delta (300MHz): 1.46 (1.2H, s), 1.48 (1.2H, s), 1.52 (1.8H, s), 1.66 (1.8H, s),2.96 (1.2H, s), 3.17 (1.8H, s), 4.08 (1H, overlapping multiplets), 4.24(0.4H, s), 4.30 (0.6H, s), 4.4-5.1 (3H, overlapping multiplets), 5.49(1H, d, J=4 Hz), 7.3-7.5 (5H, aromatics).

EXAMPLE E29 Sodium6-beta-[S-1-(N-Methyl-N-phenylcarbamoyl)-1-hydroxymethylpenicillanate

By the method of Example E6, title product of Example C17 (0.163 g.) wasconverted to instant title product, 0.10 g.; ¹ H-nmr (D₂ O) delta (300MHz): 1.40 (3H, s), 1.50 (3H, s), 3.34 (3H, s), 4.06 (1H, overlappingdoublets), 4.18 (1H, s), 4.52 (1H, d, J=10 Hz), 5.43 (1H, d, J=4 Hz),7.4-7.7 (5H, aromatic).

EXAMPLE E30 Sodium6-beta-[S-1-(N-Benzyl-N-(2-hydroxyethylcarbamoyl-1-hydroxymethyl]penicillanate

By the method of Example E6, title product of Example C18 (0.19 g.) wasconverted to instant title product, 0.11 g.; ¹ H-nmr (D₂ O) delta (300MHz): 1.42 (1.4H, s), 1.48 (1.4H, s), 1.52 (1.6H, s), 1.66 (1.6H, s),3.2-3.9 (4H, overlapping multiplets), 4.06 (1H, overlapping multiplets),4.23 (0.46H, s), 4.32 (0.54H, s), 4.6-5.2 (3H, overlapping multiplets),5.51 (1H, d, J=4 Hz), 7.2-7.6 (5H, aromatics), reflecting a mixture ofamide rotamers in about 17:20 ratio.

EXAMPLE E31 Sodium6-beta-[S-1-(4-Phenylpiperazinocarbonyl)-1-hydroxymethyl]penicillanate

By the method of Example E6, title product of Example C19 (0.16 g.) wasconverted to instant title product, 27 mg.; ir (KBr) 1781, 1763 cm⁻¹ ; ¹H-nmr (D₂ O) delta (300 MHz): 1.51 (2H, s), 1.52 (1H, s), 1.57 (2H, s),1.62 (1H, s), 1.4-2.0 (4H, overlapping multiplets), 2.7-3.0 (2H,overlapping multiplets), 3.1-3.5 (1H, overlapping multiplets), 4.05 (1H,dd, J=4 Hz, 10 Hz), 4.30 (1H, s), 3.9-4.6 (2H, overlapping multiplets),5.04 (1/3H, d, J=10 Hz), 5.05 (2/3H, d, J=10 Hz), 5.49 (1/3H, d, J=4Hz), 5.52 (2/3H, d, J=4 Hz), 7.2-7.6 (5H, aromatic, reflecting amiderotamers in about 2:1 ratio.

EXAMPLE E32 Sodium6-beta-[S-1-(Dibenzylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example E6, title product of Example C20 (262 mg.) wasconverted to instant title product, 28 mg.; ir (KBr) 1753 cm⁻¹ ; ¹ H-nmr(D₂ O) delta (300 MHz): 1.42 (3H, s), 1.46 (3H, s), 4.14 (1H, dd, J=4Hz, 9 Hz), 4.22 (1H, s), 4.2-5.0 (5H, overlapping multiplets), 5.52 (1H,d, J=4 Hz), 6.9-7.5 (10H, aromatic).

EXAMPLE E33 Sodium6-beta-[S-1-(L-2-(Hydroxymethyl)pyrrolidinocarbonyl)-1-hydroxymethyl]penicillanate

By the method of Example E6, title product of Example C21 (253 mg.) wasconverted to instant title product, 65 mg.; ¹ H-nmr (D₂ O) delta (300MHz): 1.54 (3H, s), 1.69 (2H, s), 1.71 (1H, s), 1.9-2.2 (4H, overlappingmultiplets), 3.5-3.9 (4H, overlapping multiplets), 4.06 (0.67H, dd, J=4Hz, 10 Hz), 4.12 (0.33 H, dd, J=4 Hz, 9 Hz), 4.19 (0.67H, multiplet),4.31 (1H, s), 4.43 (0.33H, multiplet), 4.88 (0.67H, d, J=10 Hz), 4.93(0.33H, d, J=9 Hz), 5.41 (0.33H, d, J=4 Hz), 5.46 (0.67H, d, J=4 Hz),reflecting a mixture of two amide rotamers in a 1:2 ratio.

EXAMPLE E34 Disodium6-beta-[S-1-(L-Prolinocarbonyl)-1-hydroxymethyl]penicillanate

By the method of Example E6, but with double the level of catalyst andNaHCO₃, title product of Example C22 (200 mg.) was converted to instanttitle product, 85 mg.; ir (KBr) 1767 cm⁻¹ ; ¹ H-nmr (D₂ O) delta (300MHz): 1.50 (3H, s), 1.65 (1.5H, s), 1.66 (1.5H, s), 1.8-2.5 (4H,overlapping multiplets), 3.6-4.2 (3H, overlapping multiplets), 4.270(0.5H, s), 4.274 (0.5H, s), 4.6-5.1 (2H, overlapping multiplets), 5.40(0.5H, d, J=4 Hz), 5.44 (0.5H, d, J=4 Hz), reflecting amide rotamers in1:1 ratio.

EXAMPLE E35 Sodium6-beta-[S-1-(N-Cyclohexyl-N-methylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example E6, title product of Example C23 (100 mg.) wasconverted to instant title product, 40 mg.; ¹ H-nmr (D₂ O) delta (300MHz): 1.50 (3H, s), 1.65 (3H, s), 1.0-2.0 (10H, overlapping multiplets),2.87 (1.5H, s), 3.10 (1.5H, s), 4.26 (1H, s), 3.8-4.3 (2H, overlappingmultiplets), 4.95 (0.5H, d, J=10 Hz), 5.02 (0.5H, d, J=10 Hz), 5.4-5.5(1H, overlapping multiplets), reflecting the two amide rotamers in about1:1 ratio.

EXAMPLE E36 Sodium6-beta-[S-1-(N-Benzyl-N-phenylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example E6, except to wash the recovered catalyst cakewith extra THF, title product of Example C24 (160 mg.) was converted toinstant freeze dried title product, all of which was taken up in ethylacetate to leave 16 mg. of a mixture of insoluble products. The ethylacetate solution (about 5 ml.) wash stripped and the residue taken up in0.5 ml. CHCl₃ and 15 ml. H₂ O. The pH was adjusted from 5.0 to 3.0 withdilute HCl. The aqueous layer was freeze dried to yield title product,37 mg.; ¹ H-nmr (D₂ O) delta (300 MHz): 1.41 (3H, s), 1.50 (3H, s), 4.09(1H, dd, J=4 Hz, 10 Hz), 4.18 (1H, s), 4.55 (1H, d, J=10 Hz), 4.86 (1H,d, J32 15 Hz), 5.11 (1H, d, J= 15 Hz), 5.48 (1H, d, J=4 Hz), 7.4-7.4(10H, aromatic), a single amide rotamer predominating.

EXAMPLE E37 Sodium6-beta-[S-1-(N-Benzyl-N-ethylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example E6, title product of Example C25 (200 mg.) wasconverted to instant title product, 45 mg.; ¹ H-nmr (D₂ O) delta (300MHz) 1.10 (1.2H, t), 1.27 (1.8H, t), 1.45 (1.2H, s), 1.47 (1.2H, s),1.52 (1.8H, s), 1.66 (1.8H, s), 3.2-3.7 (2H, overlapping multiplets),4.0-4.1 (1H, overlapping multiplets), 4.21 (0.4H, s), 4.29 (0.6H, s),4.4-5.1 (3H overlapping multiplets), 5.46 (1H, d, J=4 Hz), 7.2-7.6 (5H,aromatic), reflecting amide rotamers (conformations) in a ratio of about2:3.

EXAMPLE E38 Sodium6-beta-[S-1-(4-Hydroxypiperidinocarbonyl)-1-hydroxymethyl]penicillanate1,1-Dioxide

Without adjusting the pH (which was 3.7) before freeze drying, themethod of Example E6 was used to convert title product of Example D5 (55mg., 0.11 mmol) was converted to instant title product, 25 mg.; ¹ H-nmr(D₂ O) delta (300 MHz): 1.43 (3H, s), 1.3-1.7 (2H, complex multiplet),1.56 (3H, s), 1.9-2.1 (2H, complex multiplet), 2.9-3.5 (2H, overlappingmultiplets), 3.7-4.3 (4H, overlapping multiplets), 4.34 (1H, s), 5.16(1H, d, J=5 Hz), 5.42 (1H, overlapping doublets), indicating thepresence of the two amide rotamers in about 1:1 ratio.

EXAMPLE E39 Sodium6-beta-[S-1-(N-Benzyl-N-methylcarbamoyl)-1-hydroxymethyl]penicillanate1,1-Dioxide

By the method of the preceding Example (the pH was 5.0), title productof Example D6 (33 mg., 0.066 mmol) was converted to instant titleproduct, 15 mg.; ¹ H-nmr (D₂ O) delta (300 MHz): 1.45 (3H, s), 1.57 (3H,s), 2.87 (0.9H, s), 3.12 (2.1H, s), 4.2-4.5 (3H, complex multiplet),4.6-5.0 (1H, multiplet partially obscured by HOD peak), 5.20 (1H,overlapping doublets), 5.48 (1H, overlapping doublets), 7.2-7.6 (5H,aromatics), reflecting the presence of the two amide rotomers in about3:7 ratio.

EXAMPLE E40 Sodium6-beta-[S-1-(N-(2-Phenylethyl)-N-methylcarbamoyl)-1-hydroxymethyl]penicillanate1,1-Dioxide

By the method of Example E6, title product of Example D7 (40 mg., 0.077mmol) was converted to instant title product, 18 mg.; ¹ H-nmr (D₂ O)delta (300 MHz): 1.47 (3H, s), 1.59 (3H, s), 2.94 (1H, s), 3.06 (2H, s),2.7-3.2 (2H, overlapping multiplets), 3.5-4.0 (2H, overlappingmultiplets), 4.25 (1H, multiplet), 4.34 (1H, s), 5.18 (1H, d, J=5 Hz),5.36 (2/3H, d, J=10 Hz), 5.41 (1/3H, d, J=10 Hz), 7.2-7.7 (5H,aromatic), reflecting the amide rotamers in about 2:1 ratio.

EXAMPLE E41 Sodium6-beta-[S-1-(1,2,3,4-Tetrahydroisoquinolinocarbonyl)-1-hydroxymethyl]penicillanate1,1-Dioxide

By the method of Example E6, title product of Example D8 (0.12 g., 0.23mmol) was converted to instant title product, 33 mg.; ir (KBr) 1778 cm⁻¹; ¹ H-nmr (D₂ O) delta (300 MHz): 1.45 (3H, s), 1.54 (3H, s), 3.09 (2H,t), 4.06 (2H, t), 4.33 (1H, s), 4.36 (1H, dd, J=5 Hz, 10 Hz), 5.27 (1H,d, J=5 Hz), 5.98 (1H, d, J=10 Hz), 7.42 (1H, d), 7.50 (1H, t), 7.68 (1H,t), 8.13 (1H, d), representing the dominant amide rotamer composingabout 90% of the rotamer mixture.

EXAMPLE E42 Sodium6-beta-[S-1-(N-Methyl-N-phenylcarbamoyl)-1-hydroxymethyl]penicillanate1,1-Dioxide

By the method of Example E6, title product of Example D9 (0.14 g., 0.29mmol) was converted to instant title product, 50 mg.; ¹ H-nmr (D₂ O)delta (300 MHz): 1.46 (3H, s), 1.57 (3H, s), 3.33 (3H, s), 4.22 (1H, s),4.28 (1H, dd, J=5 Hz, 10 Hz), 5.05 (1H, d, J=10 Hz), 5.18 (1H, d, J=5Hz), 7.3-7.7 (5H, aromatics), a single amide rotamer predominating.

EXAMPLE E43 Sodium6-beta-[S-1-(4-Phenylpiperazinocarbonyl)-1-hydroxymethyl]penicillanate1,1-Dioxide

By the method of Example E6, title product of Example D10 (0.11 g., 0.23mmol) was converted to instant title product, 30 mg.; ¹ H-nmr (D₂ O)delta (300 MHz): 1.46 (1.8H, s), 1.48 (1.2H, s), 1.54 (1.8H, s), 1.60(1.2H, s), 1.7-1.9 (4H, complex), 2.6-3.3 (4H, complex), 4.0-4.3 (2H,complex), 4.33 (0.6H, s), 4.35 (0.4H, s), 4.4-4.5 (1H, complex), 5.19(1H, d, J=5 Hz), 5.46 (0.4H, d, J=10 Hz), 5.52 (0.6H, d, J=10 Hz),7.1-7.4 (5H, aromatic complex), reflecting the two amide conformers inabout 2:3 ratio.

EXAMPLE E44 Disodium6-beta-[S-1-(L-Prolinocarbonyl)-1-hydroxymethyl]penicillanate1,1-Dioxide

By the method of Example E6, title product of Example D11 (0.16 g., 0.27mmol) was converted to instant title product, 40 mg.; ¹ H-nmr (D₂ O)delta (300 MHz): 1.42 (3H, s), 1.56 (3H, s), 1.9-2.3 (4H, complex),3.5-4.3 (4H, complex), 4.31 (1H, s), 4.63 (1H, d), 5.13 (1H, d, J=4 Hz),5.18 (1H, d, J=10 Hz), a single amide rotamer predominating.

EXAMPLE E45 Sodium6-beta-[S-1-(N-Cyclohexyl-N-methylcarbamoyl)-1-hydroxymethyl]penicillanate1,1-Dioxide

By the method of Example E6, title product of Example D12 (81 mg., 0.16mmol) was converted to instant title product, 15 mg.; ¹ H-nmr (D₂ O)delta (300 MHz): 1.42 (3H, s), 1.56 (3H, s), 1.0-1.9 (10H, complex),2.84 (1.5H, s), 3.03 (1.5H, s), 3.7-4.2 (2H, complex), 4.22 (1H, dd, J=5Hz, J=10 Hz), 4.28 (1H, s), 5.16 (1H, overlapping doublets), 5.33 (0.5H,d, J=10 Hz), 5.42 (0.5H, d, J=10 Hz), reflecting the two amide rotamersin about 1:1 ratio.

EXAMPLE E46 Sodium6-beta-[S-1-(Isoindolinocarbonyl)-1-hydroxymethyl]penicillanate

By the method of Example E16, but removing a white solid from theaqueous residue after THF strip and washing the filtrate of the aqueousresidue with 5 ml. ethyl acetate prior to freeze drying, title productof Example C27 (0.25 g., 0.54 mmol) was converted to instant titleproduct, 0.125 g.; ir (KBr) 1758, 1732 cm⁻¹ ; ¹ H-nmr (D₂ O) delta (300MHz): 1.48 (3H, s), 1.66 (3H, s), 4.09 (1H, dd, J=4 Hz, 10 Hz), 4.31(1H, s), 4.72 (2H, s), 4.91 (1H, d, J=10 Hz), 5.05 (2H, ABq), 5.47 (1H,d, J=4 Hz), 7.39 (4H, s).

EXAMPLE E47 Sodium6-beta-[S-1-(4-Phenylpiperazinocarbonyl)-1-hydroxymethyl]penicillanate

By the method of Example E16, title product of Example C26 (0.4 g., 0.79mmol) was converted to instant title product, 80 mg.; ¹ H-nmr (D₂ O)delta (300 MHz): 1.53 (3H, s), 1.68 (3H, s), 3.1-4.3 (9H, overlappingcomplexes), 4.32 (1H, s), 5.10 (1H, d, J=10 Hz), 5.52 (1H, d, J=4 Hz),7.1-7.6 (5H, aromatic).

EXAMPLE E48 Sodium6-beta-[S-1-(N-(2-Hydroxyethyl)-N-phenylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example E16, title product of Example C28 (0.13 g.,0.27 mmol) was converted to instant title product, 57 mg.; ¹ H-nmr (D₂O) delta (300 MHz) (predominantly 1 amide conformer): 1.49 (3H, s), 1.64(3H, s), 3.49 (2H, complex), 3.93 (1H, dd, J=4 Hz, 10 Hz), 4.24 (1H, s),4.39 (2H, complex), 4.76 (1H, d, J=10 Hz), 5.42 (1H, d, J=4 Hz), 6.8-7.4(5H, aromatics).

EXAMPLE E49 Sodium6-beta-[S-1-(N-(Ethoxycarbonylmethyl)-N-benzylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example E16, title product of Example C29 (0.371 g.,0.68 mmol) was converted to instant title product 110 mg.; ¹ H-nmr (D₂O) delta (300 MHz) (reflecting the 2 amide conformers in about 3:2ratio): 1.27 (1.8H, t), 1.29 (1.2H, t), 1.54 (1.8H, s), 1.56 (1.2H, s),1.58 (1.8H, s), 1.68 (1.2H, s), 4.0-4.5 (6H, complex) 4.7-5.1 (3H,complex), 5.52 (0.6H, d, J=4 Hz), 5.56 (0.4H, d, J=4 Hz), 7.3-7.6 (5H,aromatics).

EXAMPLE E50 Sodium6-beta-[S-1-(N-(Dimethylcarbamoylmethyl)-N-benzylcarbamoyl-1-hydroxymethyl]penicillanate

By the method of Example E6, title product of Example C30 (0.232 g.,0.43 mmol) was converted to instant title product, 57 mg.; ir (KBr) 1757cm⁻¹ ; ¹ H-nmr (D₂ O) delta (300 MHz) (reflecting the 2 amide conformersin about 2:1 ratio): 1.45 (2H, s), 1.46 (2H, s), 1.50 (1H, s), 1.62 (1H,s), 2.90 (3H, s), 2.92 (3H, s), 4.0-5.1 (7H, complex), 5.44 (0.67H, d,J=4 Hz), 5.47 (0.33H, d, J=4 Hz), 7.3-7.5 (5H, aromatics).

EXAMPLE E51 Sodium6-beta-[S-1-(N-(Methylcarbamoylmethyl)-N-benzylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example E6, title product of Example C32 (0.34 g., 0.65mmol) was converted to instant title product, 178 mg.; ir (KBr) 1755cm⁻¹ ; ¹ H-nmr (D₂ O) delta (300 MHz) (reflecting the two amideconformers in about 1:1 ratio): 1.52 (4.5H, br.s), 1.66 (1.5H, s), 2.73(1.5H, s), 2.77 (1.5H, s), 3.9-5.1 (7H, complex), 5.51 (0.5H, d, J=4Hz), 5.54 (0.5H, d, J=4 Hz), 7.3-7.6 (5H, aromatics).

EXAMPLE E52 Sodium6-beta-[S-1-(N-Methyl-N-(4-methoxyphenyl)carbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example E6, title product of Example C33 (0.53 g., 1.1mmol) was converted to instant title product, 0.3 g.; ¹ H-nmr (D₂ O)delta (300 MHz) (reflecting predominantly a single amide conformer):1.41 (3H, s), 1.52 (3H, s), 3.28 (3H, s), 3.90 (3H, s), 4.07 (1H, dd,J=4 Hz, 10 Hz), 4.20 (1H, s), 4.51 (1H, d, J=10 Hz), 5.42 (1H, d, J=4Hz), 7.29 (4H, ABq).

EXAMPLE E53 Sodium6-beta-[S-1-(N-Methyl-N-(4-methylphenyl)carbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example E6, title product of Example C31 (0.55 g., 1.18mmols) was converted to instant title product, 0.35 g.; ¹ H-nmr (D₂ O)delta (300 MHz): 1.38 (3H, s), 1.49 (3H, s), 2.38 (3H, s), 3.28 (3H, s),4.04 (1H, dd, J=4 Hz, 10 Hz), 4.16 (1H, s), 4.50 (1H, d, J=10 Hz), 5.40(1H, d, J=4 Hz), 7.38 (4H, s).

EXAMPLE E54 Sodium6-beta-[S-1-(4-(2-Pyridyl)piperazinocarbonyl)-1-hydroxymethyl]penicillanate

By the method of Example E16, title product of Example C34 (0.42 g.,0.82 mmol) was converted to instant title product, 0.2 g.; ¹ H-nmr (D₂O) delta (300 MHz): 1.48 (3H, s), 1.64 (3H, s), 3.4-3.9 (8H, complex),4.04 (1H, dd, J=4 Hz, 10 Hz), 4.18 (1H, s), 5.03 (1H, d, J=10 Hz), 5.47(1H, d, J=4 Hz), 6.90 (1H, t), 6.97 (1H, d), 7.75 (1H, t), 8.13 (1H, d).

EXAMPLE E55 Sodium6-beta-[S-1-(Indolinocarbonyl)-1-hydroxymethyl]penicillanate

By the method of Example E6, but using a double load of catalyst, titleproduct of Example C35 (100 mg., 0.21 mmol) was converted to instanttitle product, 45 mg.; ¹ H-nmr (D₂ O) delta (300 MHz) predominantly asingle amide conformer): 1.50 (3H, s), 1.68 (3H, s), 3.28 (2H, t), 4.15(1H, dd, J=4 Hz, 9 Hz), 4.33 (1H, s), 4.38 (2H, complex), 5.00 (1H, d,J=9 Hz), 5.52 (1H, d, J=4 Hz), 7.2-7.5 (3H, complex), 8.04 (1H, d, J=8Hz).

EXAMPLE E56 Sodium6-beta-[S-1-(N-(Pyrrolidinocarbonylmethyl)-N-benzylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example E6, title product of Example C36 (0.317 g.,0.56 mmol) was converted to instant title product, 0.15 g.; ¹ H-nmr (D₂O) delta (300 MHz) (reflecting the 2 amide conformers in 1:3 ratio):1.51 (3.6H, s), 1.54 (1.2H, s), 1.66 (1.2H, s), 1.8-2.0 (4H, complex),3.3-3.5 (4H, complex), 3.9-4.2 (2H, complex), 4.26 (0.6H, s), 4.30(0.4H, s), 4.4-5.1 (5H, complex), 5.49 (0.6H, d, J=4 Hz), 5.53 (0.4H, dJ=4 Hz), 7.3-7.6 (5H, complex).

EXAMPLE E57 Sodium6-beta-[S-1-(N-Benzyl-N-isopropylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example E16, title product of Example C37 (0.31 g.,0.63 mmol) was converted to instant title product, 0.15 g.; ¹ H-nmr (D₂O) delta (300 MHz) (reflecting two amide conformers in 3:7 ratio): 1.07(1.8H, overlapping d), 1.27 (4.2H, overlapping d), 1.40 (0.9H, s), 1.49(0.9H, s), 1.54 (2.1H, s), 1.70 (2.1H, s), 4.05 (1H, complex), 4.19(0.3H, s), 4.32 (0.7H, s), 4.5-4.8 (4H, complex), 5.47 (1H, overlappingd), 7.3-7.5 (5H, complex).

EXAMPLE E58 Sodium6-beta-[S-1-(N-(2-(2-Pyridyl)ethyl)-N-methylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example E16, title product of Example C38 (0.7 g., 1.45mmols) was converted to instant title product, 0.41 g.; ¹ H-nmr (D₂ O)delta (300 MHz) (reflecting the 2 amide conformers in 1:3 ratio): 1.47(0.75H, s), 1.49 (2.25H, s), 1.62 (3H, s), 2.97 (0.75H, s), 3.22 (2.25H,s), 3.31 (2H, complex), 3.6-4.2 (3.25H, complex), 4.24 (0.75H, s), 4.72(0.25H, d, J=10 Hz), 4.88 (0.75H, d), 5.26 (0.75H, d, J=4 Hz), 5.38(0.25H, d, J=4 Hz), 7.6-8.7 (4H, heteroaromatics).

EXAMPLE E59 Sodium6-beta-[S-1-(N-Ethoxycarbonylmethyl-N-methylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example E6, title product of Example C39 (0.59, 1.3mmol) was converted to instant title product, 0.3 g.; ¹ H-nmr (D₂ O)delta (300 MHz) (reflecting amide conformers in 1:2 ratio): 1.36 (3H,complex), 1.56 (3H, s), 1.68 (1H, s), 1.72 (2H, s), 3.08 (1H, s), 3.36(2H, s), 4.0-4.5 (6H, complex), 4.9-5.1 (1H, doublets), 5.50 (1H,complex).

EXAMPLE E60 Sodium6-beta-[S-1-(N-Pyrrolidinocarbonylmethyl)-N-methylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example E6, title product of Example C40 (0.39 g., 0.8mmol) was converted to instant title product, 0.17 g.; ¹ H-nmr (D₂ O)delta (300 MHz) (reflecting amide conformers in 1:2 ratio): 1.54 (3H,s), 1.65 (1H, s), 1.70 (2H, s), 2.00 (4H, complex), 3.03 (1H, s), 3.30(2H, s), 3.50 (4H, complex), 4.07 (1H, complex), 4.1-4.4 (3H, complex),5.09 (1H, d, J=10 Hz), 5.48 (1H, complex).

EXAMPLE E61 Sodium6-beta-[S-1-(N,N-bis-(Ethoxycarbonylmethyl)carbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example E6, title product of Example C41 (0.30 g., 0.56mmol) was converted to instant title product, 60 mg.; ¹ H-nmr (D₂ O)delta (300 MHz): 1.34 (6H, complex), 1.55 (3H, s), 1.70 (3H, s), 4.0-4.6(10H, complex), 5.01 (1H, d, J=10 Hz), 5.54 (1H, d, J=4 Hz).

EXAMPLE E62 Sodium6-beta-[S-1-(N-Dimethylcarbamoylmethyl)-N-methylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example E6, title product of Example C42 (0.50 g., 1.1mmol) was converted to instant title product, 176 mg.; ¹ H-nmr (D₂ O)delta (300 MHz) (reflecting the 2 amide conformers in 3:7 ratio): 1.54(3H, br.s), 1.66 (0.9H, s), 1.70 (2.1H, s), 3.00 (3H, s), 3.02 (0.9H,s), 3.10 (3H, s), 3.28 (2.1H, s), 4.07 (1H, dd, J=4 Hz, 10 Hz), 5.47(0.7H, d, J=4 Hz), 5.50 (0.3H, d, J=4 Hz).

EXAMPLE E63 Sodium6-beta-[S-1-(N-(Methylcarbamoylmethyl)-N-methylcarbamoyl]-1-hydroxymethyl]penicillanate

By the method of Example E6, title product of Example C43 (0.50 g., 1.1mmol) was converted to instant title product 0.32 g.; ¹ H-nmr (D₂ O)delta (300 MHz), reflecting the two amide conformers in 1:2 ratio: 1.53(3H, s), 1.64 (1H, s), 1.69 (2H, s), 2.80 (2H, s), 2.84 (1H, s), 3.04(1H, s), 3.30 (2H, s), 4.0-4.1 (3H, complex), 4.31 (0.33H, s), 4.32(0.67H, s), 5.07 (0.67H, d, J=10 Hz), 5.48 (0.67H, d, J=4 Hz), 5.51(0.33H, d, J=4 Hz).

EXAMPLE E64 Sodium6-beta-[S-1-(N-(Carbamoylmethyl)-N-methylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example E6, title product of Example C44 (0.32 g., 0.73mmol) was converted to instant title product, 0.18 g.; ¹ H-nmr (D₂ O)delta (300 MHz), reflecting the 2 amide conformers in 3:7 ratio: 1.54(3H, br.s), 1.66 (0.9H, s), 1.70 (2.1H, s), 3.06 (0.9H, s), 3.32 (2.1H,s), 4.07 (1H, complex), 4.17 (1.4H, s), 4.32 (0.3H, s), 4.34 (0.7H, s),4.42 (0.6H, ABq), 5.09 (0.7H, d, J=10 Hz), 5.49 (0.7H, d, J=4 Hz), 5.53(0.3H, d, J=4 Hz).

EXAMPLE E65 Sodium6-beta-[R-1-(N-Methyl-N-phenylcarbamoyl)-1-hydroxymethyl]penicillanate

By the method of Example E6, title product of Example C45 (0.43 g., 0.95mmol) was converted to instant title product, 0.31 g.; ¹ H-nmr (D₂ O)delta (300 MHz): 1.16 (3H, s), 1.43 (3H, s), 3.38 (3H, s), 4.07 (1H, dd,J=4 Hz, 10 Hz), 4.10 (1H, s), 4.79 (1H, d, J=10 Hz), 5.48 (1H, d, J=4Hz), 7.3-7.7 (5H, complex).

EXAMPLE E66 Sodium6-beta-[S-1-(N-Benzyl-N-ethylcarbamoyl)-1-hydroxymethyl]penicillanate1,1-Dioxide

By the method of Example E6, title product of Example D13 (0.14 g., 0.27mmol) was converted to instant title product, 70 mg.; ¹ H-nmr (D₂ O)delta (300 MHz), reflecting the 2 amide conformers in 4:7 ratio: 1.04(1.1H, t), 1.20 (1.9H, t), 1.44 (3H, s), 1.56 (1.1H, s), 1.57 (1.9H, s),3.2-3.6 (2H, overlapping multiplets), 4.2-4.9 (4H, complexes), 5.17(0.64H, d, J=5 Hz), 5.20 (0.36H, d, J=5 Hz), 5.42 (0.36H, d, J=10 Hz),5.47 (0.64H, d, J=10 Hz), 7.2-7.6 (5H, multiplet).

EXAMPLE E67 Sodium6-beta-[S-1-(N-Methyl-N-(4-methoxyphenyl)carbamoyl)-1-hydroxymethyl]penicillanate1,1-Dioxide

By the method of Example E16, title product of Example D14 (0.1 g., 0.19mmol) was converted to instant title product, 55 mg.; ¹ H-nmr (D₂ O)delta (300 MHz), reflecting predominantly a single amide conformer: 1.46(3H, s), 1.57 (3H, s), 3.29 (3H, s), 3.89 (3H, s), 4.22 (1H, s), 4.27(1H, dd, J=5 Hz, 10 Hz), 5.01 (1H, d, J=10 Hz), 5.15 (1H, d, J=5 Hz),7.24 (4H, ABq).

Using the method of E1-E67 above, the following additional compoundswere prepared. Shown in sequence is the Example No., the compound, theamount prepared (as a white, lyophilized powder, unless otherwisespecified), and the starting material and amount thereof.

E68. Sodium6-beta-[S-1-(S-2-(methoxycarbonyl)pyrrolidinocarbonyl)-1-hydroxymethyl]penicillanate;0.33 g.; ir (KBr) 1774, 1747 cm⁻ ; ¹ H-nmr (D₂ O) delta (300 MHz), 1.57(3H, s), 1.73 (3H, s), 1.9-2.5 (4H, complex), 3.67 (1H, complex), 3.84(3H, s), 3.94 (2H, complex), 4.07 (1H, dd, J=4 Hz, 10 Hz), 4.96 (1H, d,J=10 Hz), 5.48 (1H, d, J=4 Hz); product of Example C46 (0.52 g.).

E69. Sodium6-beta-[S-1-(N-carbamoylmethyl-N-benzylcarbamoyl)-1-hydroxymethyl]penicillanate;0.17 g; ir (KBr) 1756, 1747 cm⁻¹ ; ¹ H-nmr (D₂ O) delta (300 MHz),reflecting two amide conformers in 3:4 ratio, 1.52 (3.4H, s), 1.56(1.3H, s), 1.68 (1.3H, s), 3.9-4.4 (4H, complex), 4.5-5.2 (3H, complex),5.52 (0.57H, d, J=4 Hz), 5.55 (0.43H, d, J=4 Hz), 7.3-7.6 (5H, complex);product of Example C47 (0.31 g.) E70. Sodium6-beta-[S-1-(N,N-di(N-methylcarbamoylmethyl)carbamoyl)-1-hydroxymethyl]penicillanate;78 mg.; ir (KBr) 1750 cm⁻¹ ; ¹ H-nmr (D₂ O) delta (300 MHz), 1.55 (3H,s), 1.65 (3H, s), 2.82 (3H, s), 2.86 (3H, s), 4.0-4.4 (5H, complex),4.63 (1H, d, J=17 Hz), 4.83 (1H, d, J=11 Hz), 5.50 (1H, d, J=4 Hz);product of Example C48 (0.15 g).

E71. Sodium6-beta-[S-1-(N-ethyl-N-phenylcarbamoyl)-1-hydroxymethyl]penicillanate;0.16 g.; ¹ H-nmr (D₂ O) delta (300 MHz), 1.17 (3H, t), 1.43 (3H, s),1.52 (3H, s), 3.77 (2H, m), 4.05 (1H, dd, J=4 Hz, 10 Hz), 4.18 (1H, s),4.46 (1H, d, J=10 Hz), 5.43 (1H, d, J=4 Hz), 7.5-7.6 (5H, complex);product of Example C49 (0.39 g.).

E72. Sodium6-beta-[S-1-(1,2,3,4-tetrahydroquinolinocarbonyl)-1-hydroxymethyl]penicillanate;0.105 g.; ¹ H-nmr (D₂ O) delta (300 MHz), 1.11 (3H, s), 1.36 (3H, s),1.49 (1H, m), 1.65 (1H, m), 1.86 (1H, m), 2.11 (1H, m), 2.94 (2H, m),3.42 (1H, m), 3.7-4.3 (3H, m), 4.97 (1H, m), 5.34 (1H, m), 7.3-7.5 (4H,aromatics); product of Example C50 (0.265 g.).

E73. Sodium6-beta-[S-1-[N-ethyl-N-(4-hydroxyphenyl)carbamoyl]-1-hydroxymethyl]penicillanate;(twice hydrogenated due to incomplete removal of the phenolic benzylgroup in the initial hydrogenation); 54 mg.; ¹ H-nmr (D₂ O) delta (300MHz), 1.08 (3H, t), 1.37 (3H, s), 1.44 (3H, s), 3.65 (2H, q), 3.96 (1H,dd, J=4 Hz, 10 Hz), 4.12 (1H, s), 4.39 (1H, d, J=10 Hz), 5.36 (1H, d,J=4 Hz), 6.9-7.4 (4H, aromatics); product of Example C51 (0.40 g.).

E74. Sodium6-beta-[S-1-(N-ethyl-N-(3-hydroxyphenyl)carbamoyl)-1-hydroxymethyl]penicillanate;(twice hydrogenated since sodium6-beta-[S-1-(N-ethyl-N-(3-benzyloxyphenyl)carbamoyl)-1-hydroxymethyl]penicillanatewas found in the initial hydrogenation); 70 mg.; ¹ H-nmr (D₂ O) delta(300 MHz), 1.08 (3H, t), 1.34 (3H, s), 1.42 (3H, s), 3.67 (2H, q), 3.97(1H, dd, J=4 Hz, 10 Hz), 4.12 (1H, s), 4.40 (1H, d, J=10 Hz), 5.34 (1H,d, J=4 Hz), 6.9-7.5 (4H, aromatics); product of Example C52 (0.20 g.).

E75. Sodium6-beta-[S-1-(1-(methoxycarbonyl)isoindolinocarbonyl)-1-hydroxymethyl]penicillanate;0.120 g.; ir (KBr) 1746 cm⁻¹ ; ¹ H-nmr (D₂ O) delta (300 MHz),reflecting 1-isoindoline diastereoisomers in 1:2 ratio, 1.46 (2H, s),1.50 (1H, s), 1.64 (2H, s), 1.68 (1H, s), 3.78 (1H, s), 3.81 (2H, s),4.0-4.2 (1H, complex), 4.29 (0.67H, s), 4.32 (0.33H, s), 4.8-5.3 (4H,overlapping multiplets), 5.4-5.5 (1H, complex), 5.66 (0.33H, s), 5.70(0.67H, s), 7.4-7.5 (4H, complex); product of Example C53 (0.40 g.).

E76. Sodium6-beta-[S-1-(N-(N-isopropylcarbamoylmethyl)-N-benzyl)carbamoyl-1-hydroxymethyl]penicillanate;0.14 g.; ir (KBr) 1749, 1756 cm⁻¹ ; ¹ H-nmr (D₂ O) delta (300 MHz),reflecting two amide conformers in a ratio of about 5:7, 1.0-1.1 (6H,complex), 1.44 (1.75H, s), 1.46 (1.25H, s), 1.49 (1.75H, s), 1.59(1.25H, s), 3.7-4.3 (4H, overlapping multiplets), 4.21 (1H, s), 4.5-5.1(4H, complex), 5.4-5.5 (1H, overlapping doublets), 7.27 (1H, d), 7.3-7.5(5H, m); product of Example C54 (0.34 g.).

E77. Sodium6-beta-[S-1-(S-2-(carbamoyl)pyrrolidinocarbonyl)-1-hydroxymethyl]penicillanate;40 mg.; ir (KBr) 1769 cm⁻¹ ; ¹ H-nmr (D₂ O) delta (300 MHz), 1.50 (3H,s), 1.63 (3H, s), 1.8-2.3 (4H, complex), 3.4-3.6 (2H, complex), 4.10(1H, dd, J=4 Hz, 10 Hz), 4.31 (1H, s), 4.61 (1H, t), 5.63 (1H, d, J=10Hz), 5.67 (1H, d, J=4 Hz); product of Example C55 (0.26 g.).

E78. Sodium6-beta-[S-1-(S-2-(N-methylcarbamoyl)pyrrolidinocarbonyl)-1-hydroxymethyl]penicillanate;0.15 g.; ir (KBr) 1753 cm⁻¹ ; ¹ H-nmr (D₂ O) delta (300 MHz) 1.55 (3H,s), 1.71 (3H, s), 1.9-2.4 (4H, complex), 3.8-4.0 (2H, complex), 4.04(1H, dd, J=4 Hz, 10 Hz), 4.32 (1H, s), 4.40 (1H, m), 4.94 (1H, d, J=10Hz), 5.47 (1H, d, J=4 Hz); product of Example C56 (0.26 g.).

E79. Sodium6-beta-[S-1-(N,N-di(pyrrolidinocarbonylmethyl)carbamoyl)-1-hydroxymethyl]penicillanate;0.29 g.; ¹ H-nmr (D₂ O) delta (300 MHz), 1.49 (3H, s), 1.61 (3H, s),1.8-2.1 (8H, complex), 3.3-3.6 (8H, complex), 4.03 (1H, dd, J=4 Hz, 10Hz), 4.22 (2H, ABq), 4.26 (1H, s), 4.52 (2H, ABq), 4.86 (1H, d, J=10Hz), 5.46 (1H, d, J=4 Hz); product of Example C57 (0.40 g.).

E80. Sodium6-beta-[S-1-[N-(4-(2-hydroxyethyl)piperazinocarbonylmethyl)-N-benzylcarbamoyl]-1-hydroxymethyl]penicillanate;14 mg; ¹ H-nmr (D₂ O) delta (300 MHz), reflecting two amide conformersin 1:1 ratio, 1.40 (1.5H, s), 1.42 (1.5H, s), 1.54 (1.5H, s), 1.56(1.5H, s), 2.6-2.9 (4H, complex), 3.1-3.4 (2H, complex), 3.5-4.1 (8H,complex), 4.1-4.5 (4H, complex), 4.93 (1H, br.d), 5.39 (0.5H, d, J=4Hz), 5.42 (0.5H, d, J=4 Hz), 7.43 (5H, br.s); product of Example C58 (19mg.).

E81. Sodium6-beta-[S-1-(4-(N-isopropylcarbamoylmethyl)piperazinocarbonyl)-1-hydroxymethyl]penicillanate;0.22 g.; ir (KBr) 1758 cm⁻¹ ; ¹ H-nmr (D₂ O) delta (300 MHz), 1.11 (6H,d), 1.44 (3H, s), 1.58 (3H, s), 3.0-3.2 (4H, complex), 3.62 (2H, br.s),3.7-4.0 (6H, complex), 4.22 (1H, s), 4.95 (1H, d, J=10 Hz), 5.43 (1H, d,J=4 Hz); product of Example C59 (0.387 g.). E82. Sodium6-beta-[S-1-(2,6-dimethylmorpholinocarbonyl)-1-hydroxymethyl]penicillanate;0.116 g.; ir (KBr) 1762 cm⁻¹ ; ¹ H-nmr (D₂ O) delta (300 MHz),reflecting two isomers in 1:1 ratio, possible the two amide conformersof a single meso-2,6-dimethylmorpholino isomer, 1.19 (6H, d), 1.46 (3H,s), 1.60 (3H, s), 2.54 (1H, m), 2.98 (1H, m), 3.6-4.3 (6H, overlappingmultiplets), 4.91 (0.5H, d, J=10 Hz), 5.01 (0.5H, d, J=10 Hz), 5.41(0.5H, d, J=4 Hz), 5.43 (0.5H, d, J=4 Hz); product of Example C60 (0.26g.).

E83. Sodium6-beta-[S-1-(N-(N-ethylcarbamoylmethyl)-N-benzylcarbamoyl)-1-hydroxymethyl]penicillanate;0.100 g.; ir (KBr) 1753 cm⁻¹ ; ¹ H-nmr (D₂ O) delta (300 MHz),reflecting two amide rotamers in 2:3 ratio, 1.01 (3H, complex), 1.44(1.8H, s), 1.46 (3H, s), 1.58 (1.2H, s), 3.0-3.2 (2H, complex), 4.21(1H, s), 3.8-5.0 (6H, complex), 5.44 (0.6H, d, J=4 Hz), 5.47 (0.4H, d,J=4 Hz), 7.3-7.5 (5H, m); product of Example C61 (0.20 g.).

E84. Sodium6-beta-[S-1-(N-(1-methyl-4-piperidyl)-N-methylcarbamoyl)-1-hydroxymethyl]penicillanate;60 mg.; ir (KBr) 1757 cm⁻¹ ; ¹ H-nmr (D₂ O) delta (300 MHz), reflectingtwo amide rotamers in 1:2 ratio, 1.44 (3H, s), 1.58 (3H, s), 1.8-2.2(4H, complex), 2.82 (1H, s), 2.86 (3H, s), 3.06 (2H, s), 3.0-3.3 (2H,complex), 3.5-3.7 (2H, complex), 3.96 (1H, dd, J=4 Hz, 10 Hz), 4.22 (1H,s), 4.46 (1H, complex), 4.88 (0.7H, d, J=10 Hz), 4.96 (0.3H, d, J=10Hz), 5.39 (0.7H, d, J=4 Hz), 5.41 (0.3H, d, J=4 Hz); product of ExampleC62 (162 mg.).

E85. Sodium6-beta-[S-1-(N-(2-morpholinoethyl)-N-benzylcarbamoyl)-1-hydroxymethyl]penicillanate;89 mg.; ir (KBr) 1748 cm⁻¹ ; ¹ H-nmr (D₂ O) delta (300 MHz), reflectingtwo amide rotamers in 2:3 ratio, 1.42 (3.6H, s), 1.46 (1.2H, s), 1.62(1.2H, s), 2.5-2.9 (6H, complex), 3.6-3.8 (6H, complex), 4.00 (1H,complex), 4.18 (0.6H, s), 4.25 (0.4H, s), 4.4-5.0 (3H, complex), 5.45(1H, d, J=4 Hz), 7.4 (5H, complex); product of Example C63 (166 mg.).

E86. Sodium6-beta-[S-1-(4-(2-hydroxyethyl)pipierazinocarbonyl)-1-hydroxymethyl]penicillanate;66 mg.; ¹ H-nmr (D₂ O) delta (300 MHz), 1.43 (3H, s), 1.58 (3H, s),2.8-3.1 (6H, complex), 3.6-3.9 (6H, complex), 3.95 (1H, dd, J=4 Hz, 10Hz), 4.21 (1H, s), 4.96 (1H, d, J=10 Hz), 5.41 (1H, d, J=4 Hz); productof Example C64 (0.14 g.).

E87. Sodium6-beta-[S-1-(4-benzylpiperazinocarbonyl)-1-hydroxymethyl]penicillanate;165 mg; ir (KBr) 1751 cm⁻¹ ; ¹ H-nmr (D₂ O) delta (300 MHz), 1.42 (3H,s), 1.55 (3H, s), 2.8-3.1 (4H, complex), 3.2-3.4 (1H, complex), 3.5-3.9(3H, complex), 3.94 (1H, dd, J=4 Hz, 10 Hz), 4.05 (2H, s), 4.20 (1H, s),4.91 (1H, d, J=10 Hz), 5.39 (1H, d, J=4 Hz), 7.46 (5H, br.s); product ofExample C65 (346 mg.).

E88. Sodium6-beta-[S-1-(N-(N-ethylcarbamoylmethyl)-N-ethylcarbamoyl)-1-hydroxymethyl]penicillanate;40 mg.; ir (KBr) 1749 cm⁻¹ ; ¹ H-nmr (D₂ O) delta (300 MHz), reflectingtwo amide rotamers in 1:2 ratio, 1.08 (3H, complex), 1.23 (3H, t), 1.46(3H, s), 1.57 (1H, s), 1.62 (2H, s), 3.20 (3H, complex), 3.38 (1H, q),3.59 (2H, complex), 3.9-4.1 (3H, complex), 4.21 (0.33H, s), 4.24 (0.67H,s), 4.26 (1H, q), 4.98 (1H, d, J=10 Hz), 5.40 (0.67H, d, J=4 Hz), 5.42(0.33H, d, J=4 Hz); product of Example C66 (0.13 g.).

E89. Sodium6-beta-[S-1-(N-(N-propylcarbamoylmethyl)-N-benzylcarbamoyl)-1-hydroxymethyl)penicillanate;90 mg; ir (KBr) 1750 cm⁻¹ ; ¹ H-nmr (D₂ O) delta (300 MHz), reflectingthe two amide rotamers in 2:3 ratio, 0.84 (3H, overlapping triplets),1.42 (2H, complex), 1.47 (1.8H, s), 1.49 (3H, s), 1.61 (1.2H, s),3.0-3.2 (2H, complex), 3.8-4.3 (4H, complex), 4.5-5.1 (3H, complex),5.46 (0.6H, d, J=4 Hz), 5.49 (0.4H, d, J=4 Hz), 7.2-7.5 (5H, arom.);product of Example C67 (0.32 g.).

E90. Sodium6-beta-[S-1-(2-(N-ethylcarbamoyl)pyrrolidino)carbonyl]-1-hydroxymethyl]penicillanate;120 mg; ir (KBr) 1756 cm⁻¹ ; ¹ H-nmr (D₂ O) delta (300 MHz), reflectingtwo amide rotamers in 1:5 ratio, 1.08 (3H, t), 1.47 (3H, s), 1.61 (0.5H,s), 1.63 (2.5H, s), 1.8-2.1 (3H, complex), 2.2-2.3 (1H, complex),3.1-3.3 (2H, complex), 3.5-3.7 (2H, complex), 3.97 (1H, dd, J=4 Hz, 10Hz), 4.26 (1H, s), 4.32 (1H, m), 4.64 (0.17H, d), 4.87 (0.83H, d, J=10Hz), 5.40 (0.83H, d, J=4 Hz), 5.43 (0.17H, d, J=4 Hz); product ofExample C68 (225 mg.).

E91. Sodium6-beta-[S-1-[N-(N-(2-methylpropyl)carbamoylmethyl)-N-(2-methylpropyl)carbamoyl]-1-hydroxymethyl]penicillanate;60 mg.; ir (KBr) 1754 cm⁻¹ ; ¹ H-nmr (D₂ O) delta (300 MHz), reflectingtwo amide rotamers in 1:1 ratio, 0.88 (9H, d), 0.9-1.0 (3H, complex),1.48 (3H, s), 1.60 (1.5H, s), 1.62 (1.5H, s), 1.7-2.1 (2H, complex),2.9-3.1 (2H, complex), 3.2-3.4 (1.5H, complex), 3.5-3.6 (0.5H, complex),4.0-4.2 (2H, complex), 4.22 (0.5H, s), 4.26 (0.5H, s), 4.35 (1H, q),4.80 (0.5H, d), 4.95 (0.5H, d), 5.44 (1H, m); product of Example C69(0.12 g.).

E92. Sodium6-beta-[S-1-(N-(2-morpholinoethyl)-N-ethylcarbamoyl)-1-hydroxymethyl]penicillanate;50 mg.; ¹ H-nmr (D₂ O) delta (300 MHz), reflecting two amide rotamers inabout 1:2 ratio, 1.09 (1H, t), 1.25 (2H, t), 1.45 (3H, s), 1.61 (3H, s),2.0-3.1 (6H, complex), 3.2-4.0 (9H, complex), 4.24 (1H, s), 4.8-5.0 (1H,complex), 5.41 (1H, complex); product of Example C70 (0.11 g.). E93.Sodium6-beta-[S-1-[N-(R-alpha-methylbenzyl)carbamoyl]-1-hydroxymethyl]penicillanate;0.13 g.; ¹ H-nmr (D₂ O) delta (300 MHz), 1.44 (3H, s), 1.46 (3H, d),1.60 (3H, s), 3.81 (1H, dd, J=4 Hz, 10 Hz), 4.20 (1H, s), 4.66 (1H, d,J=10 Hz), 4.91 (1H, q, J=8 Hz), 5.34 (1H, d, J=4 Hz), 7.3-7.4 (5H, m);product of Example C71 (0.23 g.)

E94. Sodium6-beta-[S-1-[N-(S-alpha-methylbenzyl)carbamoyl]-1-hydroxymethyl]penicillanate;0.115 g.; ¹ H-nmr (D₂ O) delta (300 MHz) 1.44 (3H, s), 1.47 (3H, d, J=6Hz), 3.88 (1H, dd, J=4 Hz, 10 Hz), 4.20 (1H, s), 4.62 (1H, d, J=10 Hz),4.91 (1H, q), 5.37 (1H, d, J=4 Hz), 7.3-7.4 (5H, complex); product ofExample C72 (0.18 g.).

E95. Sodium6-beta-[S-1-(N-benzhydrylcarbamoyl)-1-hydroxymethyl]penicillanate;initially isolated as the free acid from the aqueous residue followingTHF stripping, by acidification to pH 5.5 with 1N HCl, extraction intoethyl acetate, drying over Na₂ SO₄, and stripping, 0.16 g.; converted tothe sodium salt by dissolving in 10 ml. H₂ O, adjusting to pH 6.0 with1N NaOH and freeze drying, 0.16 g.; ¹ H-nmr (D₂ O) delta (300 MHz), 1.43(3H, s), 1.58 (3H, s), 3.85 (1H, dd, J=4 Hz, J=10 Hz), 4.15 (1H, s),4.65 (1H, d, J=10 Hz), 5.30 (1H, d, J=4 Hz), 5.98 (1H, s), 7.1-7.3 (10H,complex); product of Example C73 (0.23 g.).

E96. Sodium6-beta-[S-1-(N-[N-(2-morpholinoethyl)carbamoylmethyl]-N-benzylcarbamoyl)-1-hydroxymethyl]penicillanate;0.164 g.; ir (KBr) 1754 cm⁻¹ ; ¹ H-nmr (D₂ O) delta (300 MHz),reflecting two amide rotamers in about 1:2 ratio, 1.46 (2H, s), 1.49(1H, s), 1.50 (2H, s), 1.62 (1H, s), 3.0-3.3 (6H, complex), 3.5-3.6 (2H,complex), 3.9-4.1 (6H, complex), 4.22 (0.67H, s), 4.30 (0.33H, s), 4.46(0.33H, d, J=15 Hz), 4.9-5.0 (1H, complex), 5.02 (0.67H, d, J=10 Hz),5.44 (0.67H, d, J=4 Hz), 5.47 (0.33H, d, J=4 Hz), 7.2-7.5 (5H, complex);product of Example C74 (0.23 g.).

E97. Sodium6-beta-[S-1-(S-2-(N,N-dimethylcarbamoyl)pyrrolidinocarbonyl)-1-hydroxymethyl]penicillanate;0.18 g.; ir (KBr) 1753 cm⁻¹ ; ¹ H-nmr (D₂ O) delta (300 MHz), reflectingamide rotamers in about 1:5 ratio, 1.60 (3H, s), 1.76 (3H, s), 1.9-2.0(1H, multiplet), 2.1-2.2 (2H, complex), 2.4-2.5 (1H, multiplet), 3.04(3H, s), 3.26 (3H, s), 3.7-4.0 (3H, complex), 4.1 (1H, dd, J=4 Hz, 10Hz), 4.36 (1H, s), 5.00 (1H, d, J=10 Hz), 5.49 (1H, d, J=4 Hz); productof Example C75 (0.33 g.).

E98. Sodium6-beta-[S-1-(1,4-diazabicyclo[3.2.2]-non-4-ylcarbonyl)-1-hydroxymethyl]penicillanate;0.050 g.; ir (KBr) 1751 cm⁻¹ ; ¹ H-nmr (D₂ O) delta (300 MHz),reflecting amide rotamers in about 1:3 ratio, 1.46 (3H, s), 1.80 (3H,s), 2.0-2.4 (4H, complex), 3.4-3.6 (8H, complex), 3.97 (0.75H, dd, J=4Hz, 10 Hz), 4.01 (0.25H, dd, J=4 Hz, 10 Hz), 4.1 (2H, complex), 4.23(1H, s), 4.95 (0.25H, d, J=10 Hz), 4.96 (0.75H, d, J=10 Hz), 5.41(0.25H, d, J=4 Hz), 5.44 (0.75H, d, J=4 Hz); product of Examplee C76(0.11 g.).

E99. Sodium6-beta-[S-1-(S-2-(pyrrolidinocarbonyl)pyrrolidinocarbonyl)-1-hydroxymethyl]penicillanate;0.18 g.; ir (KBr) 1763 cm⁻ ; ¹ H-nmr (D₂ O) delta (300 MHz),predominantly a single amide rotamer, 1.46 (3H, s), 1.62 (3H, s),1.8-2.4 (8H, complex), 3.3-3.9 (6H, complex), 3.95 (1H, dd, J=4 Hz, 10Hz), 4.22 (1H, s), 4.62 (1H, m), 4.85 (1H, d, J=10 Hz), 5.34 (1H, d, H=4Hz); product of Example C77 (0.32 g.).

E100. Sodium6-beta-[S-1-(N-methyl-N-(4-hydroxyphenyl)carbamoyl)-1-hydroxymethyl]penicillanate;0.075 g.; ¹ H-nmr (D₂ O) delta (300 MHz), 1.46 (3H, s), 1.61 (3H, s),2.70 (3H, s), 4.09 (1H, dd, J=4 Hz, 10 Hz), 4.22 (1H, s), 4.96 (1H, d,J=10 Hz), 5.50 (1H, d, J=4 Hz), 6.88 (4H, ABq); product of Example C78(0.21 g.).

E101. Sodium6-beta-[S-1-[N-(R-alpha-methylbenzyl)carbamoyl]-1-hydroxymethyl]penicillanate1,1-dioxide; 0.054 g.; ¹ H-nmr (D₂ O) delta (300 MHz), 1.34 (3H, s),1.44 (3H, d, J=8 Hz), 1.50 (3H, s), 3.94 (1H, dd, J=5 Hz, 11 Hz), 4.20(1H, s), 4.88 (1H, d, J≡Hz), 4.93 (1H, q, J=8 Hz), 5.10 (1H, d, J=11Hz), 7.2-0.74 (5H, complex); product of Example D15 (0.11 g.).

MISCELLANEOUS REACTIONS EXAMPLE F1 Pivaloyloxymethyl6-beta-[S-1-(1,2,3,4-tetrahydroisoquinolino)carbonyl-1-hydroxymethyl]penicillanate

The title product of Example E16 (0.245 g., 0.59 mmol) was dissolved in1 ml. DMF and cooled to 0° C. Chloromethyl pivalate (0.086 ml., 0.089g., 0.59 mmol) was added and the mixture stirred for 18 hours at roomtemperature, then equilibrated with 10 ml. H₂ O and 10 ml. ether. Theorganic layer was separated and filtered (yielding 50 mg. of solids).The aqueous layer was extracted with 2×10 ml. of ether, and the filteredorganic layer and ether extracts combined, washed 1×10 ml. H₂ O and 1×10ml. brine, dried over Na₂ SO₄ and stripped to a foam, 90 mg., which tlcindicated to be incompletely esterified. The solids and the foam wereredissolved in 1 ml. of fresh DMF and cooled to 0° C.Diisopropylethylamine (0.053 ml., 0.039 g.) and then chloromethylpivalate (0.049 ml., 0.051 g.) were added and the mixture stirred 18hours at room temperature, then isolated according to the procedureabove (in this case, no product precipitated from the initial etherlayer) to yield an oil, 0.24 g., which was chromatographed on 10 g.silica gel using 1:3 ethyl acetate:CHCl₃ as eluant to produce purifiedtitle product as a foam, 0.11 g.; ¹ H-nmr (CDCl₃) delta (300 MHz),reflecting amide rotamers in about 2:3 ratio, 1.20 (9H, s), 1.44 (1.2H,s), 1.46 (1.8H, s), 1.61 (1.2H, s), 1.65 (1.8H, s), 2.8-3.0 (2H,complex), 3.6-3.8 (2H, complex), 3.85-4.00 (1H, complex), 4.05-4.15 (1H,complex), 4.44 (0.4H, s), 4.46 (0.6H, s), 4.7-5.0 (3H, complex), 5.54(1H, m), 5.77 (1H, d), 5.87 (1H, d), 7.1-7.3 (4H, complex).

PREPARATION F1 Sodium Salt of Benzyl6-beta-(S-1-Carboxy-1-hydroxymethyl)penicillanate

Title product of Preparation B1 (11.1 g., 0.0274 mol) was dissolved in100 ml. CH₂ Cl₂. Sodium 2-ethylhexanoate in ethyl acetate (0.5N, 54.8ml., 0.0274 mol) and then Pd[(C₆ H₅)₃ P]₄ (0.4 g.) were added, themixture was stirred 1 hour under N₂, diluted with 300 ml. ether, andfiltered to yield instant title product, 10.1 g.; ¹ H-nmr (D₂ O) delta(300 MHz): 1.37 (3H, s), 1.63 (3H, s), 3.86 (1H, dd, J=4 Hz, 10 Hz),4.45 (1H, d, J=10 Hz), 4.62 (1H, s), 5.28 (2H, ABq), 5.51 (1H, d, J=4Hz), 7.5 (5H, s).

PREPARATION F2 Sodium Salt of Benzyl6-beta-(R-1-Carboxy-1-hydroxymethyl)penicillanate

By the method of the preceding Preparation, title product of PreparationB2 (5.48 g., 0.0135 mol) was converted to instant title product, 3.85g.; ¹ H-nmr (D₂ O) delta (300 MHz): 1.38 (3H, s), 1.65 (3H, s), 4.05(1H, dd, J=4 Hz, 8 Hz), 4.44 (1H, d, J=10 Hz), 4.61 (1H, s), 5.28 (2H,ABq), 5.49 (1H, d, J=4 Hz), 7.50 (5H, s).

The cyclic anhydrides employed in the preceding Examples were isolatedand characterized as follows:

PEREPARATION F3 6-beta-(S-1,3-dioxolane-2,5-dion-4-yl)penicillanate

Title product of Preparation F1 (0.271 g., 0.7 mmol) was dissolved in 20ml. dry THF and cooled to -15° C. COCl₂ in CCl₄ (0.7N, 1.5 ml., 1.05mmols) was added. After 1 minute, solvent was stripped to produce a nearquantitative yield of instant title product as a dry foam, ir (CHCl₃)1900, 1820 and 1780 cm⁻¹ ; ¹ H-nmr (CDCl₃) delta (300 MHz): 1.44 (3H,s), 1.68 (3H, s), 4.24 (1H, overlapping doublets), 4.56 (1H, s), 5.22(2H, s), 5.46 (1H, d, J=5 Hz), 5.59 (1H, d, J=4 Hz), 7.40 (5H, s).

PREPARATION F4 6-beta-(R-1,3-dioxolane-2,5-dion-4-yl)penicillanate

By the procedure of the preceding Preparation, R-title product ofPreparation F2 (0.271 g., 0.7 mmol) was converted to instant titleproduct, again in quantitative yield; ir (CHCl₃) 1900, 1817 and 1780cm⁻¹ ; ¹ H-nmr (CDCl₃) delta (300 MHz): 1.44 (3H, s), 1.67 (3H, s), 4.27(1H, overlapping doublets), 4.57 (1H, s), 5.21 (2H, s), 5.56 (2H,complex), 7.40 (5H, s).

PREPARATION F5 Diallyl Tartarate

Tartaric acid (450 g., 3.0 mols) was slurried in 600 ml. DMF and cooledto 0°-5° C. in an ice bath. Triethylamine (835 ml., 6.0 mols) was addedand the resulting solution recooled to 0°-5° C. Allyl bromide (519 ml.,6.0 mols) was then added. An exotherm was noted. The resulting slurrywas stirred at room temperature and by-product triethylaminehydrobromide recovered by filtration. The filtrate was diluted with 1.5l. of ethyl acetate, washed 3×300 ml. H₂ O, dried over Na₂ SO₄ andstripped to yield title product as an oil, 434 g.; ¹ H-nmr (CDCl₃) delta3.42 (2H, br.s), 4.5-4.8 (6H, complex), 5.0-5.4 (4H, complex), 5.6-6.2(2H, complex).

PREPARATION F6 Allyl 2-Methoxy-2-hydroxyacetate (Allyl Glyoxylate MethylAcetal)

The product of the preceding Preparation (161 g., 0.74 mol) wasdissolved in a mixture of 133 ml. acetic acid and 800 ml. H₂ O, stirredand cooled to 0°-5° C. A slurry of NaIO₄ (157.3 g., 0.74 mol) in 700 ml.H₂ O was added over a 10 minute period. The resulting solution wasstirred at 0°-5° C., a heavy precipitate beginning to form after 30minutes. After 1 hour, the mixture was filtered. The cake was washedwith 1 l. ethyl acetate and the wash liquor combined with the filtrate.The aqueous layer was separated and washed 3×800 ml. fresh ethylacetate. The organic layer and three extracts were combined andstripped, the residue taken up in 1 l. ether and washed 2×300 ml. H₂ O.The latter H₂ O extracts were combined and extracted with 300 ml. ethylacetate. The combined ether layer and ethyl acetate extract werestripped to yield allyl 2,2-dihydroxyacetate (allyl glyoxylate hydrate)as an oil. The hydrate was dissolved in 1 l. CH₃ OH and stripped, andthe process repeated several times, to yield the present hemiacetalproduct as an oil, 148 g.; ¹ H-nmr (CDCl₃) delta 3.45 (3H, s), 4.6-6.3(6H, complex).

PREPARATION F7 Allyl Glyoxalate

The product of the preceding Preparation (105 g.) was heated at 65° C.under vacuum (0.8 mm) under a reflux condenser for 20 hours, then vacuumdistilled and redistilled to yield present title product, 37 g., ¹ H-nmr(CDCl₃) delta 4.60 (2H, d), 5.0-5.4 (2H, complex), 5.5-6.2 (1H, m), 9.34(1H, s).

PREPARATION F8 Tartaric Acid bis-Pyrrolidine Amide

Pyrrolidine (61 ml., 0.73 mol) and diethyl tartrate (50 ml., 0.29 mol)were stirred for 5 minutes and then allowed to stand for 3 days. Theresulting solid mass was broken up by the addition of an equal volume ofethyl acetate and title product recovered by filtration, 54 g., mp132°-134° C.; ¹ H-nmr (CDCl₃) delta (ppm) 1.7-2.1 (8H, complex), 3.3-3.7(8H, complex), 4.2-4.6 (4H, complex).

Other amines were reacted with diethyl tartarate to form bis-tartrateamides useful in the present syntheses. Dimethylamine reacted morerapidly than pyrrolidine, while other secondary amines reacted moreslowly.

PREPARATION F9 N-Glyoxyloylpyrrolidine

Title product of the preceding Preparation (20 g., 0.08 mol) wasdissolved in 200 ml. benzene. Lead tetraacetate (95%, 36.4 g., 0.08 mol)was added slowly. After stirring for 1 hour, by-products were removed byfiltration, the filtrate stripped and the residue distilled at 0.15 mm.from a bath at 100°-125° C. Title product was collected in threefractions, 11.87 g.; ¹ H-nmr (CDCl₃) delta (ppm) 1.8-2.2 (4H, complex),3.4-3.9 (4H, complex), 9.37 (1H, s). The material was used in furtherprocessing within a few hours.

PREPARATION F10 N-Isopropylglyoxylamide

By the method of the preceding Preparation, tartaroylbis-(N-isopropylamide) (20 g., 0.086 mol) was converted to titleproduct, 12.2 g.; bp 70°-72° 2 mm; ¹ H-nmr (CDCl₃) delta (ppm) 1.24 (6H,d, J=7 Hz), 4.00 (1H, m), 9.24 (1H, s).

PREPARATION F11 N-Glyoxyloylmorpholine

By the method of Preparation F9, tartaric acid bis-morpholine amide(11.45 g., 0.04 mol) was converted to title product. The residue wasdistilled at 1.5 mm from a bath at 120°-130°, collecting title productin two fractions (4.74 g.), used immediately in further processing; ¹H-nmr (CDCl₃) delta (ppm) 3.5-3.9 (8H, complex), 9.43 (1H, s).

PREPARATION F12 N-Glyoxyloylpiperidine

By the method of Preparation F9, tartaric acid bis-piperidine amide(20.6 g., 0.072 mol) was converted to title product. The residue wasdistilled at 1.1 mm. from a bath at 110°-130°, collecting title productin 3 fractions, 13.74 g.; ¹ H-nmr (CDCl₃) delta (ppm) 1.4-1.8 (6H,complex), 3.3-3.8 (4H, complex), 9.55 (1H, s).

PREPARATION F13 N,N-Dimethylglyoxylamide

Tartaroyl bis-(dimethylamide) (30 g., 0.15 mol) was converted to titleproduct by the method of Preparation F9. The residue was distilled froma bath at 70° at a pressure from 1.5 to 0.8 mm. The initial fraction(about 5-7 ml.) was discarded. The second and third fractions (11 and 7g., respectively) represented good quality title product; ¹ H-nmr(CDCl₃) delta (ppm) 3.05 (3H, s), 3.23 (3H, s), 9.46 (1H, s).

I claim:
 1. A compound having the formula ##STR25## wherein n is 0, 1 or2;R is hydrogen, a radical group forming an ester hydrolyzable underphysiological conditions, or an acyloxymethyl or 1-(acyloxy)ethylradical derived from a conventional beta-lactam antibiotic; and R¹ andR² are taken separately and are each independently hydrogen, (C₁-C₇)alkyl, phenyl, (C₇ -C₁₂)phenylalkyl, (C₃ -C₇)cycloalkyl, naphthyl,or ##STR26## where m is 1 or 2 and p is 1, 2 or 3; or one of said groupssubstituted on aliphatic, aromatic or heterocyclic carbon with (C₁-C₄)alkyl, phenyl, hydroxy, hydroxymethyl, 2-hydroxyethyl, (C₁-C₄)alkoxy, (C₂ -C₅)alkanoyloxy, carbamoyloxy, formamido, (C₂-C₅)alkanecarboxamido, (C₁ -C₄)alkanesulfonamido, ##STR27## onheterocyclic nitrogen with (C₁ -C₄)alkyl, phenyl, (C₇ -C₉)phenylalkyl,pyridyl, 2-hydroxyethyl, formyl, (C₂ -C₅)alkanoyl; or ##STR28## R¹ andR² are taken together with the nitrogen to which they are attached toform a pyrrolidine, piperidine, perhydroazepine, morpholine, piperazine,homopiperazine, indoline, isoindoline, 1,2,3,4-tetrahydroquinoline,1,2,3,4-tetrahydroisoquinoline or ##STR29## ring system; or one of saidring systems substituted on aliphatic, aromatic or heterocyclic carbonwith (C₁ -C₄)alkyl, phenyl, hydroxy, hydroxymethyl, 2-hydroxyethyl, (C₁-C₄)alkoxy, (C₂ -C₅)alkanoyloxy, carbamoyloxy, formamido, (C₂-C₅)alkanecarboxamido, (C₁ -C₄)alkanesulfonamido, ##STR30## onheterocyclic nitrogen with (C₁ -C₄)alkyl, phenyl, (C₇ -C₉)phenylalkyl,pyridyl, 2-hydroxyethyl, formyl, (C₂ -C₅)alkanoyl; or ##STR31## R³ andR⁴ are taken separately and are each hydrogen, (C₁ -C₄)alkyl or phenyl;or R³ and R⁴ are taken together with the nitrogen to which they areattached to form a pyrrolidine, piperidine, morpholine, or 4-[(C₁-C₃)alkyl or phenyl]piperazine ring; with the provisos that in saidgroup --NR¹ R² (a) there is no tetrahedral carbon atom which issimultaneously bonded to two of the same or different atoms selectedfrom the group consisting of nitrogen, oxygen or sulfur and (b) whenboth of R¹ and R² are other than hydrogen, then the carbons of R¹ and R²which are adjacent to the nitrogen branch point are substituted with atotal of at least two hydrogens; a pharmaceutically acceptable cationicsalt when the compound contains a carboxylic acid group; or apharmaceutically acceptable acid addition salt when the compoundcontains a basic nitrogen atom.
 2. A compound of claim 1 wherein R ishydrogen.
 3. A compound of claim 1 wherein R¹ and R² are takenseparately and are each independently hydrogen, (C₁ -C₄)alkyl, (C₅-C₆)cycloalkyl, phenyl, benzyl or one of said groups substituted bymethyl, hydroxy, (C₁ -C₂)alkoxy, --COOR³, or --CONR³ R⁴.
 4. A compoundof claim 3 wherein the C-1 hydroxy substituted carbon of the side chainis in the S-configuration.
 5. A compound of claim 3 wherein R ishydrogen.
 6. A compound of claim 4 wherein R is hydrogen.
 7. A compoundof claim 3 wherein n is
 0. 8. A compound of claim 5 wherein n is
 0. 9. Acompound of claim 6 wherein n is
 0. 10. The compound of claim 9 whereinR¹ and R² are each methyl.
 11. The compound of claim 9 wherein R¹ ismethyl and R² is benzyl.
 12. The compound of claim 9 wherein R¹ ismethyl and R² is phenyl.
 13. The compound of claim 9 wherein R¹ isbenzyl and R² is --CH₂ CONHCH₃.
 14. The compound of claim 9 wherein R¹is ethyl and R² is 3-hydroxyphenyl.
 15. A compound of claim 6 wherein nis
 1. 16. The compound of claim 15 wherein R¹ and R² are each methyl andthe 1-oxide is in the beta-configuration.
 17. A compound of claim 6wherein n is
 2. 18. The compound of claim 17 wherein R¹ and R² are eachmethyl.
 19. The compound of claim 17 wherein R¹ is methyl and R² isphenyl.
 20. The compound of claim 17 wherein R¹ is methyl and R² iscyclohexyl.
 21. A compound of claim 1 wherein R¹ and R² are takentogether with the nitrogen to which they are attached to form apyrrolidine, piperidine, perhydroazepine, morpholine, 4-[formyl, (C₁-C₄)alkyl, phenyl, benzyl, pyridyl or 2-hydroxyethyl]piperazine,indoline, isoindoline, 1,2,3,4-tetrahydroquinoline or1,2,3,4-tetrahydroisoquinoline ring system, or one of said ring systemssubstituted by methyl, hydroxy, hydroxymethyl, carboxy, carbamoyl,--COOR³ or --CONR³ R⁴.
 22. A compound of claim 21 wherein the C-1hydroxy substituted carbon of the side chain is in the S-configuration.23. A compound of claim 21 wherein R is hydrogen.
 24. A compound ofclaim 22 wherein R is hydrogen.
 25. A compound of claim 21 wherein n is0.
 26. A compound of claim 23 wherein n is
 0. 27. A compound of claim 24wherein n is
 0. 28. The compound of claim 27 wherein R¹ R² N-- isperhydroazepino.
 29. The compound of claim 27 wherein R¹ R² N-- is1,2,3,4-tetrahydroisoquinolino.
 30. The compound of claim 27 wherein R¹R² N-- is isoindolino.
 31. The compound of claim 27 wherein R¹ R² N-- isindolino.
 32. The compound of claim 27 wherein R¹ R² N-- is piperidino.33. A compound of claim 24 wherein n is
 1. 34. The compound of claim 33wherein R¹ R² N-- is pyrrolidine and the 1-oxide is in the alphaconfiguration.
 35. A compound of claim 24 wherein n is
 2. 36. Thecompound of claim 35 wherein R¹ R² N-- is piperidino.
 37. The compoundof claim 35 wherein R¹ R² N-- is 4-hydroxypiperidino.
 38. The compoundof claim 35 wherein R¹ R² N-- is 4-phenylpiperidino.
 39. A compound ofclaim 1 wherein R is a radical group forming an ester hydrolyzable underphysiological conditions.
 40. A compound of claim 4 wherein R is aradical group forming an ester hydrolyzable under physiologicalconditions.
 41. A compound of claim 40 wherein Ris:(5-methyl-1,3-dioxol-2-on-4-yl)methyl; 1H-isobenzofuran-3-on-1-yl;gamma-butyrolacton-4-yl; --CHR⁵ OCOR⁶ ; or --CHR⁵ OCOOR⁷ ; wherein R⁵ ishydrogen or methyl; R⁶ is (C₁ -C₆)alkyl, (C₁ -C₆)carboxyalkyl,carboxycyclohexyl or carboxyphenyl; and R⁷ is (C₁ -C₆)alkyl.
 42. Acompound of claim 41 wherein R is 1-(ethoxycarbonyloxy)ethyl orpivaloyloxymethyl.
 43. A compound of claim 22 wherein R is a radicalgroup forming an ester hydrolyzable under physiological conditions. 44.A compound of claim 43 wherein Ris:(5-methyl-1,3-dioxol-2-on-4-yl)methyl; 1H-isobenzofuran-3-on-1-yl;gamma-butyrolacton-4-yl; --CHR⁵ OCOR⁶ ; or --CHR⁵ OCOOR⁷ ; wherein R⁵ ishydrogen or methyl; R⁶ is (C₁ -C₆)alkyl, (C₁ -C₆)carboxyalkyl,carboxycyclohexyl or carboxyphenyl; and R⁷ is (C₁ -C₆)alkyl.
 45. Acompound of claim 44 wherein R is 1-(ethoxycarbonyloxy)ethyl orpivaloyloxymethyl.
 46. A compound of claim 1 wherein R is anacyloxymethyl radical derived from a conventional beta-lactamantibiotic.
 47. A compound of claim 4 wherein R is an acyloxymethylradical derived from a conventional beta-lactam antibiotic.
 48. Acompound of claim 47 wherein R is an acyloxymethyl radical of theformula ##STR32## wherein Y is hydrogen or hydroxy.
 49. A compound ofclaim 48 wherein Y is hydrogen.
 50. A compound of claim 22 wherein R isan acyloxymethyl radical derived from a conventional beta-lactamantibiotic.
 51. A compound of claim 50 wherein R¹ is an acyloxymethylradical of the formula ##STR33## wherein Y is hydrogen or hydroxy.
 52. Acompound of claim 51 wherein Y is hydrogen.
 53. A pharmaceuticalcomposition comprising an antibacterially effective amount of a compoundof claim 1 and a pharmaceutically acceptable carrier or diluent.
 54. Apharmaceutical composition comprising an antibacterially effectiveamount of a compound of claim 3 and a pharmaceutically acceptablecarrier or diluent.
 55. A pharmaceutical composition comprising anantibacterially effective amount of a compound of claim 6 and apharmaceutically acceptable carrier or diluent.
 56. A pharmaceuticalcomposition comprising an antibacterially effective amount of a compoundof claim 21 and a pharmaceutically acceptable carrier or diluent.
 57. Apharmaceutical composition comprising an antibacterially effectiveamount of a compound of claim 24 and a pharmaceutically acceptablecarrier or diluent.
 58. A method of treating a bacterial infection in amammal which comprises administerint to said mammal an antibacteriallyeffective amount of a compound of claim
 1. 59. A method of treating abacterial infection in a mammal which comprises administering to saidmammal an antibacterially effective amount of a compound of claim
 3. 60.A method of treating a bacterial infection in a mammal which comprisesadministering to said mammal an antibacterially effective amount of acompound of claim
 6. 61. A method of treating a bacterial infection in amammal which comprises administering to said mammal an antibacteriallyeffective amount of a compound of claim
 21. 62. A method of treating abacterial infection in a mammal which comprises administering to saidmammal an antibacterially effective amount of a compound of claim 24.63. A pharmaceutical composition for treating bacterial infections whichcomprises, in a weight ratio of 10:1 to 1:3, a conventional beta-lactamantibiotic and a compound of claim 1 wherein R is hydrogen or a radicalgroup forming an ester which is hydrolyzable under physiologicalconditions.
 64. A pharmaceutical composition for treating bacterialinfections which comprises, in a weight ratio of 10:1 to 1:3, aconventional beta-lactam antibiotic and a compound of claim 3 wherein Ris hydrogen or a radical group forming an ester which is hydrolyzableunder physiological conditions.
 65. A pharmaceutical composition fortreating bacterial infections which comprises in a weight ratio of 10:1to 1:3, a conventional beta-lactam antibiotic and a compound of claim 6.66. A pharmaceutical composition of claim 65 wherein the beta-lactamantibiotic isamoxicillin, ampicillin, apalcillin, azlocillin, aztreonam,bacampicillin, carbenicillin, carbenicillin indanyl, carbenicillinphenyl, cefaclor, cefadroxil, cefaloram, cefamandole, cefamandolenafate, cefaparole, cefatrizine, cefazolin, cefbuperazone, cefmenoxime,cefonicid, cefodizime, cefoperazone, ceforanide, cefotaxime, cefotiam,cefoxitin, cefpimazole cefpiramide, cefpirome, cefsulodin, ceftazidime,ceftizoxime, ceftriaxone, cefuroxime, cephacetrile, cephalexin,cephaloglycin, cephaloridine, cephalothin, cephapirin, cepharadine,cyclacillin, epicillin, furazlocillin hetacillin, lenampicillin,levopropylcillin, mecillinam, mezlocillin, penicillin G, penicillin V,phenethicillin,, piperacillin, pivampicillin, sarmoxicillin,sarpicillin, suncillin, talampicillin, ticarcillin; or7-[D-(2-[4-carboxy-5-imidazolecarboxamido])-2-phenylacetamido]-3-[4-sulfonatoethyl)pyridinium]-3-cephem-4-carboxylicacid; or a pharmaceutically-acceptable salt of one of said beta-lactamantibiotics.
 67. A pharmaceutical composition for treating bacterialinfections which comprises, in a weight ratio of 10:1 to 1:3, aconventional beta-lactam antibiotic and a compound of claim 21 wherein Ris hydrogen or a radical group forming an ester which is hydrolyzableunder physiological conditions.
 68. A pharmaceutical composition fortreating bacterial infections which comprises, in a weight ratio of 10:1to 1:3, a conventional beta-lactam antibiotic and a compound of claim 24wherein R is hydrogen or a radical group forming an ester which ishydrolyzable under physiological conditions.
 69. A pharmaceuticalcomposition of claim 68 wherein the beta-lactam antibioticisamoxicillin, ampicillin, apalcillin, azlocillin, aztreonam,bacampicillin, carbenicillin, carbenicillin indanyl, carbenicillinphenyl, cefaclor, cefadroxil, cefaloram, cefamandole, cefamandolenafate, cefaparole, cefatrizine, cefazolin, cefbuperazone, cefmenoxime,cefonicid, cefodizime, cefoperazone, ceforanide, cefotaxime, cefotiam,cefoxitin, cefpimiazole, cefpiramide, cefpirome, cefsulodin,ceftazidime, ceftizoxime, ceftriaxone, cefuroxime, cephacetrile,cephalexin, cephaloglycin, cephaloridine, cephalothin, cephapirin,cephradine, cyclacillin, epicillin, furazlocillin hetacillin,lenampicillin, levopropylcillin, mecillinam, mezlocillin, penicillin G,penicillin V, phenethicillin,, piperacillin, pivampicillin,sarmoxicillin, sarpicillin, suncillin, talampicillin, ticarcillin; or7-[D-(2-[4-carboxy-5-imidazolecarboxamido])-2-phenylacetamido]-3-[4-sulfonatoethyl)pyridinium]-3-cephem-4-carboxylicacid; or a pharmaceutically-acceptable salt of one of said beta-lactamantibiotics.
 70. A method of treating a bacterial infection in a mammalwhich comprises administering to said mammal an antibacteriallyeffective amount of a pharmaceutical composition of claim
 63. 71. Amethod of treating a bacterial infection in a mammal which comprisesadministering to said mammal an antibacterially effective amount of apharmaceutical composition of claim
 64. 72. A method of treating abacterial infection in a mammal which comprises administering to saidmammal an antibacterially effective amount of a pharmaceuticalcomposition of claim
 65. 73. A method of treating a bacterial infectionin a mammal which comprises adminstering to said mammal anantibacterially effective amount of a pharmaceutical composition ofclaim
 66. 74. A method of treating a bacterial infection in a mammalwhich comprises administering to said mammal an antibacterial effectiveamount of a pharmaceutical composition of claim
 67. 75. A method oftreating a bacterial infection in a mammal which comprises administeringto said mammal an antibacterially effective amount of a pharmaceuticalcomposition of claim
 68. 76. A method of treating a bacterial infectionin a mammal which comprises administering to said mammal anantibacterially effective amount of a pharmaceutical composition ofclaim
 69. 77. A compound having the formula ##STR34## wherein n is 0, 1or 2; andR¹ and R² are taken separately and are each independentlyhydrogen, (C₁ -C₇)alkyl, phenyl, (C₇ -C₁₂)phenylalkyl, (C₃-C₇)cycloalkyl, naphthyl, or ##STR35## where m is 1 or 2 and p is 2 or3; or one of said groups substituted on aliphatic, aromatic orheterocyclic carbon with (C₁ -C₄)alkyl, phenyl, hydroxy, hydroxymethyl,2-hydroxyethyl, (C₁ -C₄)alkoxy, (C₂ -C₅)alkanoyloxy, carbamoyloxy,formamido, (C₂ -C₅)alkylcarboxamido, (C₁ -C₄)alkylsulfonamido, ##STR36##on heterocyclic nitrogen with (C₁ -C₄)alkyl, phenyl, (C₇-C₉)phenylalkyl, pyridyl, 2-hydroxyethyl, formyl, (C₂ -C₅)alkanoyl, or##STR37## or R¹ and R² are taken together with the nitrogen to whichthey are attached to form a pyrrolidine, piperidine, perhydroazepine,morpholine, piperazine, homopiperazine, indoline, isoindoline,1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline or ##STR38##ring system; or one of said ring systems substituted on aliphatic,aromatic or heterocyclic carbon with (C₁ -C₄)alkyl, hydroxy,hydroxymethyl, 2-hydroxyethyl, (C₁ -C₄)alkoxy, (C₂ -C₅)alkanoyloxy,carbamoyloxy, formamido, (C₂ -C₅)alkylcarboxamido, (C₁-C₄)alkylsulfonamido, ##STR39## or on heterocylic nitrogen with (C₁-C₄)alkyl, phenyl, (C₇ -C₉)phenylalkyl, pyridyl, 2-hydroxyethyl, formyl,(C₂ -C₅)alkanoyl, or ##STR40## R³ and R⁴ are taken separately and areeach hydrogen, (C₁ -C₄)alkyl or phenyl; or R³ and R⁴ are taken togetherwith the nitrogen to which they are attached to form a pyrrolidine,piperidine, morpholine, or 4-[(C₁ -C₃)alkyl or phenyl]piperazine ring;with the provisos (a) that said group --NR¹ R² contains no tetrahedralcarbon which is simultaneously bonded to two of the same or differentatoms selected from the group consisting of nitrogen, oxygen and sulfur;(b) when both of R¹ and R² are other than hydrogen, then the carbons ofR¹ and R² which are adjacent to the nitrogen branch point in said group--NR¹ R² are substituted with a total of at least two hydrogens; and (c)that when said group --NR¹ R² contains a substituent --NH or --NH₂ groupwhich is more reactive towards cyclic anhydride than the R¹ R² NH group,said substituent --NH or --NH₂ group is protected by a benzyloxycarbonylgroup.
 78. A compound of claim 77 wherein substituent NH or NH₂ groupsare protected by a benzyloxycarbonyl group, and substituent carboxy orphenolic hydroxy groups are protected by a benzyl group.
 79. A compoundof claim 77 wherein R¹ and R² are taken separately and are eachindependently hydrogen, (C₁ -C₄)alkyl, (C₅ -C₆)cycloalkyl, phenyl,benzyl or one of said groups substituted by methyl, hydroxy, (C₁-C₂)alkoxy, --COOR³ or --CONR³ R⁴.
 80. A compound of claim 79 whereincarboxy or phenolic hydroxy groups are protected by a benzyl group. 81.A compound of claim 79 wherein the C-1 hydroxy substituted carbon of theside chain is in the S-configuration.
 82. A compound of claim 80 whereinthe C-1 hydroxy substituted carbon of the side chain is in theS-configuration.
 83. A compound of claim 77 wherein R¹ and R² are takentogether with the nitrogen to which they are attached to form apyrrolidine, piperidine, perhydroazepine, morpholine, 4-[formyl, (C₁-C₄)alkyl, phenyl, benzyl, pyridyl or 2-hydroxyethyl]piperazine,indoline, isoindoline, 1,2,3,4-tetrahydroquinoline or1,2,3,4-tetrahydroisoquinoline ring system, or one of said ring systemssubstituted by methyl, hydroxy, hydroxymethyl, carboxy, carbamoyl,--COOR³ or --CONR³ R⁴.
 84. A compound of claim 83 wherein carboxy orphenolic hydroxy groups are protected by a benzyl group.
 85. A compoundof claim 83 wherein the C-1 hydroxy substituted carbon of the side chainis in the S-configuration.
 86. a compound of claim 84 wherein the C-1hydroxy substituted carbon of the side chain is in the S-configuration.